Substituted indole compounds useful as inhibitors of tlr7/8/9

ABSTRACT

Disclosed are compounds of Formula (I) or a salt thereof, wherein: Y is Formula (II), or Formula (III); R 1 , R 2 , R 2a , R 2b , R 2c , R 3 , R 4 , R 5 , m, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmune diseases.

The present invention generally relates to substituted indole compoundsuseful as inhibitors of signaling through Toll-like receptor 7, 8, or 9(TLR7, TLR8, TLR9) or combinations thereof. Provided herein aresubstituted indole compounds, compositions comprising such compounds,and methods of their use. The invention further pertains topharmaceutical compositions containing at least one compound accordingto the invention that are useful for the treatment of conditions relatedto TLR modulation, such as inflammatory and autoimmune diseases, andmethods of inhibiting the activity of TLR₅ in a mammal.

Toll/IL-1 receptor family members are important regulators ofinflammation and host resistance. The Toll-like receptor familyrecognizes molecular patterns derived from infectious organismsincluding bacteria, fungi, parasites, and viruses (reviewed in Kawai, T.et al., Nature Immunol.,11:373-384 (2010)). Ligand binding to thereceptor induces dimerization and recruitment of adaptor molecules to aconserved cytoplasmic motif in the receptor termed the Toll/IL-1receptor (TIR) domain. With the exception of TLR₃, all TLR₅ recruit theadaptor molecule MyD88. The IL-1 receptor family also contains acytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewedin Sims, J. E. et al., Nature Rev. Immunol., 10:89-102 (2010)).

Toll-like receptors (TLR₅) are a family of evolutionarily conserved,transmembrane innate immune receptors that participate in the first-linedefense. As pattern recognition receptors, the TLR₅ protect againstforeign molecules, activated by pathogen associated molecular patterns(PAMPs), or from damaged tissue, activated by danger associatedmolecular patterns (DAMPs). A total of 13 TLR family members have beenidentified, 10 in human, that span either the cell surface or theendosomal compartment. TLR7-9 are among the set that are endosomallylocated and respond to single-stranded RNA (TLR7and TLR8) orunmethylated single-stranded DNA containing cytosine-phosphate-guanine(CpG) motifs (TLR9).

Activation of TLR7/8/9 can initiate a variety of inflammatory responses(cytokine production, B cell activation and IgG production, Type Iinterferon response). In the case of autoimmune disorders, the aberrantsustained activation of TLR7/8/9 leads to worsening of disease states.Whereas overexpression of TLR7 in mice has been shown to exacerbateautoimmune disease, knockout of TLR7 in mice was found to be protectiveagainst disease in lupus-prone MRL/lpr mice. Dual knockout of TLR7 and 9showed further enhanced protection.

As numerous conditions may benefit by treatment involving modulation ofcytokines, IFN production and B cell activity, it is immediatelyapparent that new compounds capable of modulating TLR7 and/or TLR8and/or TLR9 and methods of using these compounds could providesubstantial therapeutic benefits to a wide variety of patients.

The present invention relates to a new class of substituted indolecompounds found to be effective inhibitors of signaling throughTLR7/8/9. These compounds are provided to be useful as pharmaceuticalswith desirable stability, bioavailability, therapeutic index, andtoxicity values that are important to their drugability.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (I) that are usefulas inhibitors of signaling through Toll-like receptor 7, 8, or 9 and areuseful for the treatment of proliferative diseases, allergic diseases,autoimmune diseases and inflammatory diseases, or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates or prodrugsthereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for inhibition of Toll-likereceptor 7, 8, or 9 comprising administering to a host in need of suchtreatment a therapeutically effective amount of at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for treating proliferative,metabolic, allergic, autoimmune and inflammatory diseases, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof.

The present invention provides a method for treating inflammatory andautoimmune diseases. Particular, inflammatory and autoimmune diseasesinclude, but are not limited to, Crohn's disease, ulcerative colitis,asthma, graft versus host disease, allograft rejection, chronicobstructive pulmonary disease, rheumatoid arthritis, systemic lupuserythematosus, lupus nephritis, cutaneous lupus, psoriasis, adult onsetStill's disease, systemic onset juvenile idiopathic arthritis, multiplesclerosis.

DETAILED DESCRIPTION

The first aspect of the present invention provides at least one compoundof Formula (I):

or a salt thereof, wherein:

-   Y is

-   R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃    hydroxy-fluoroalkyl, —CR_(z)═CH₂, C₃₋₆ cycloalkyl, —CH₂(C₃₋₆    cycloalkyl), —C(O)O(C₁₋₃ alkyl), or tetrahydropyranyl;-   R₂ is C₁₋₆ alkyl, C₁₋₃ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃    aminoalkyl, —(CH₂)₀₋₄O(C₁₋₃ alkyl), C₃₋₆ cycloalkyl,    —(CH₂)₁₋₃C(O)NR_(x)R_(x), —CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl),    tetrahydrofuranyl, tetrahydropyranyl, or phenyl;-   each R_(2a) is independently H, halo, —CN, —NR_(x)R_(x), C₁₋₆ alkyl,    C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ fluoroalkoxy,    —(CH₂)₀₋₂O(C₁₋₃ alkyl), —(CH₂)₀₋₃C(O)NR_(x)R_(x), —(CH₂)₁₋₃(C₃₋₆    cycloalkyl), —C(O)O(C₁₋₃ alkyl), —C(O)NR_(x)(C₁₋₃ alkyl),    —CR_(x)═CR_(x)R_(x), —CR_(x)═CH(C₃₋₆ cycloalkyl),    —C(O)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl,    pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted with    zero, 1, or 2 R_(y);-   each R_(y) is independently F, Cl, —CN, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, C₁₋₃ alkoxy, —NR_(x)C(O)(C₁₋₃ alkyl), —C(O)NR_(x)R_(x),    C₃₋₆ cycloalkyl, piperidinyl, or morpholinyl;-   R_(2b) is R₂ or R_(2a);-   R_(2c) is R₂ or R_(2a); provided that one of R_(2b) and R_(2c) is    R₂, and the other of R_(2b) and R_(2c) is R_(2a); R₃ is    -   (a) -L₁-A; or    -   (b) H, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃        cyanoalkyl, —(CH₂)₀₋₄O(C₁₋₃ alkyl), —(CH₂CH₂O)₂₋₃O(C₁₋₃ alkyl),        —CH₂CH₂NR_(x)R_(x), —CR_(x)R_(x)C(O)OH,        —(CR_(x)R_(x))₀₋₂C(O)NR_(x)R_(x), —CH₂C(O)NR_(x)(C₁₋₃ alkyl),        —CH₂C(O)NR_(x)(C₁₋₄ hydroxyalkyl), —(CR_(x)R_(x))₀₋₂S(O)₂(C₁₋₃        alkyl), —C(O)(C₁₋₃ alkyl), —C(O)(C₁₋₃ fluoroalkyl),        —C(O)CR_(x)R_(x)NR_(x)R_(x), —C(O)(C₁₋₆ hydroxyalkyl), or        —NR_(x)C(O)(C₁₋₃ alkyl);-   L₁ is a bond, —(CR_(x)R_(x))₁₋₂—, —(CR_(x)R_(x))₁₋₂CR_(x)(OH)—,    —(CR_(x)R_(x))₁₋₂O—, —CR_(x)R_(x)C(O)—,    —(CR_(x)R_(x))₂NR_(x)(CR_(x)R_(x))₀₋₁—,    —CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₀₋₄—, —C(O)(CR_(x)R_(x))₀₋₃—,    —C(O)(CR_(x)R_(x))₀₋₂NR_(x)(CR_(x)R_(x))₀₋₂—,    —C(O)(CR_(x)R_(x))₀₋₂NR_(x)(CR_(x)R_(x))₁₋₂CR_(x)(OH)—,    —C(O)(CR_(x)R_(x))₁₋₂C(O)NR_(x)—,    —(CR_(x)R_(x))₀₋₂C(O)NR_(x)(CR_(x)R_(x))₁₋₂CR_(x)(OH)—,    —C(O)(CR_(x)R_(x))₀₋₁O—, —C(O)(CR_(x)R_(x))₁₋₂NHS(O)₂—,    —C(O)NR_(x)(CR_(x)R_(x))₁₋₂—, or —S(O)₂(CR_(x)R_(x))₀₋₂—;-   A is adamantanyl, azepanyl, azetidinyl, C₃₋₆ cycloalkyl, diazepanyl,    dihydroinonyl, dihydropyrimidinonyl, dioxidoisothiazolidinyl,    dioxidothiazinanyl, dioxotetrahydrothiophenyl,    dioxotetrahydrothiopyranyl, dioxothiomorpholinyl, furanyl,    imidazolyl, imidazolidinonyl, indolyl, isoquinolinyl, isoxazolyl,    morpholinyl, morpholinonyl, naphthalenyl, oxazolidinonyl,    oxadiazolyl, oxetanyl, oxazolyl, phenyl, piperidinyl, piperidinonyl,    piperazinyl, piperazinonyl, pyrazinyl, pyrazolyl, pyrazolidinonyl,    pyridazinonyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidinonyl,    pyrrolidin-dionyl, pyrrolidinyl, pyrrolyl, quinolinyl,    quinolizinonyl, tetrahydrofuranyl, tetrahydrofuranonyl,    tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl, or    triazolyl, each substituted with zero, 1, or 2 R_(3a);-   each R_(3a) is independently F, Cl, —OH, —NH₂, C₁₋₃ alkyl, C₁₋₂    fluoroalkyl, or —C(O)NR_(x)R_(x);-   each R₄ is independently F, —OH, C₁₋₂ alkyl, or —OCH₃; or two R₄    attached to the same carbon atom form ═O;-   each R₅ is independently F, Cl, —CN, C₁₋₂ alkyl, C₁₋₂ fluoroalkyl,    or —OCH₃;-   each R_(x) is independently H or —CH₃;-   R_(z) is H, C₁₋₂ alkyl, or C₁₋₂ fluoroalkyl;-   m is zero, 1, 2, 3, or 4; and-   n is zero, 1, 2, or 3.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein Y is

and R₁, R₂, R_(2a), R₃, R₄, R₅, m, and n are defined in the firstaspect. Compounds of this embodiment have the structure of Formula (Ia):

Included in this embodiment are compounds in which R₁ is —CH(CH₃)₂.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein Y is

and R₁, R₂, R_(2a), R₃, R₄, R₅, m, and n are defined in the firstaspect.

Compounds of this embodiment have the structure of Formula (Ib):

Included in this embodiment are compounds in which R₁ is —CH(CH₃)₂.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein Y is

and R₁, R₂, R_(2a), R₃, R₄, R₅, m, and n are defined in the firstaspect. Compounds of this embodiment have the structure of Formula (Ic):

Included in this embodiment are compounds in which R₁ is —CH(CH₃)₂.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein Y is

and R₁, R₂, R_(2a), R₃, R₄, R₅, m, and n are defined in the firstaspect. Compounds of this embodiment have the structure of Formula (Id):

Included in this embodiment are compounds in which R₁ is —CH(CH₃)₂.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein Y is

and R₁, R₂, R_(2a), R₃, R₄, R₅, m, and n are defined in the firstaspect. Included in this embodiment are compounds in which Y is

Also included in this embodiment are compounds in which R₁ is —CH(CH₃)₂.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein Y is

and R₁, R₂, R_(2a), R_(2b), R_(2c), R₃, R₄, R₅, m, and n are defined inthe first aspect. Included in this embodiment are compounds in which R₁is —CH(CH₃)₂.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein Y is

and R₁, R₂, R_(2a), R_(2b), R_(2c), R₃, R₄, R₅, m, and n are defined inthe first aspect. Included in this embodiment are compounds in whichR_(2b) is R. Also included in this embodiment are compounds in whichR_(2b) is R_(2a). Additionally, included in this embodiment arecompounds in which R₁ is —CH(CH₃)₂.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃hydroxy-fluoroalkyl, C₃₋₆ cycloalkyl, —CH₂(C₃₋₆ cycloalkyl), —C(O)O(C₁₋₃alkyl), or tetrahydropyranyl; and R₂, R_(2a), R_(2b), R_(2c), R₃, R₄,R₅, m, and n are defined in the first aspect. Included in thisembodiment are compounds in which R₁ is H, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl,or C₃₋₆ cycloalkyl. Also included in this embodiment are compounds inwhich R₁ is —CH₂CH₃ or —CH(CH₃)₂. Additionally, included in thisembodiment are compounds in which R₁ is —CH(CH₃)₂.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₂ is C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₂aminoalkyl, —(CH₂)₀₋₄O(C₁₋₂ alkyl), C₃₋₆ cycloalkyl,—(CH₂)₁₋₂C(O)NR_(x)R_(x), —CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl),tetrahydrofuranyl, tetrahydropyranyl, or phenyl; and Y, R₁, R_(2a),R_(2b), R_(2c), R₃, R₄, R₅, R_(x), m, and n are defined in the firstaspect. Included in this embodiment are compounds in which R₂ is C₁₋₄alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₃OCH₃, C₃₋₆cycloalkyl, —CH₂C(O)NR_(x)R_(x), —CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl),tetrahydrofuranyl, or phenyl. Also included in this embodiment arecompounds in which R₂ is —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂C(CH₃)₂OH, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂OCH₃,—CH₂(cyclopropyl), —CH₂(phenyl), —CH₂C(O)NH₂, tetrahydrofuranyl, orphenyl.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is —CH(CH₃)₂; R₂ is —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂C(CH₃)₂OH, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂OCH₃,—CH₂(cyclopropyl), —CH₂(phenyl), —CH₂C(O)NH₂, tetrahydrofuranyl, orphenyl; and R_(2a), R_(2b), R_(2c), R₃, R₄, R₅, R_(x), m, and n aredefined in the first aspect. Included in this embodiment are compoundsin which Y is

One embodiment provides a compound of Formula (I) or a salt thereof,wherein each R_(2a) is independently H, F, Cl, —CN, —NR_(x)R_(x), C₁₋₆alkyl, C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ fluoroalkoxy,—(CH₂)₀₋₂O(C₁₋₃ alkyl), —(CH₂)₀₋₃C(O)NR_(x)R_(x), —(CH₂)₁₋₃(C₃₋₆cycloalkyl), —C(O)O(C₁₋₃ alkyl), —C(O)NR_(x)(C₁₋₃ alkyl),—CR_(x)═CR_(x)R_(x), —CR_(x)═CH(C₃₋₆ cycloalkyl), —C(O)(pyrrolidinyl),or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl,pyridinyl, and pyrimidinyl, each substituted with zero, 1, or 2 R_(y);and Y, R₁, R₂, R_(2b), R_(2c), R₃, R₄, R₅, R_(x), R_(y), m, and n aredefined in the first aspect. Included in this embodiment are compoundsin which each R_(2a) is independently H, F, Cl, —CN, —NR_(x)R_(x), C₁₋₆alkyl, C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl, —(CH₂)₀₋₂O(C₁₋₂ alkyl),—(CH₂)₀₋₂C(O)NR_(x)R_(x), —(CH₂)₁₋₃(cyclopropyl), —C(O)O(C₁₋₂ alkyl),—C(O)NR_(x)(C₁₋₃ alkyl), —CR_(x)═CH₂, —CH═CH(C₃₋₆ cycloalkyl),—C(O)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl,pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted withzero, 1, or 2 R_(y). Also included in this embodiment are compounds inwhich each R_(2a) is independently H, F, Cl, —CN, —NH₂, C₁₋₅ alkyl,—CF₃, —CH₂OH, —OCH₃, —CH₂OCH₃, —CH₂CH₂(cyclopropyl), —C(O)OCH₃,—C(O)N(CH₃)₂, —C(O)NH(CH₂CH₂CH₃), —CH═CH₂, —C(CH₃)═CH₂,—CH═CH(cyclopropyl), —C(O)(pyrrolidinyl), or a cyclic group selectedfrom pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, eachsubstituted with zero, 1, or 2 R_(y).

One embodiment provides a compound of Formula (I) or a salt thereof,wherein each R_(2a) is independently H, F, Cl, —CN, —NR_(x)R_(x), C₁₋₆alkyl, C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ fluoroalkoxy,—(CH₂)₀₋₂O(C₁₋₃ alkyl), —(CH₂)₀₋₃C(O)NR_(x)R_(x), —(CH₂)₁₋₃(C₃₋₆cycloalkyl), —C(O)O(C₁₋₃ alkyl), —C(O)NR_(x)(C₁₋₃ alkyl),—CR_(x)═CR_(x)R_(x), —CR_(x)═CH(C₃₋₆ cycloalkyl), —C(O)(pyrrolidinyl),or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl,pyridinyl, and pyrimidinyl, each substituted with zero, 1, or 2 R_(y);each R_(y) is independently F, Cl, —CN, C₁₋₂ alkyl, C₁₋₂ alkoxy,—NR_(x)C(O)(C₁₋₂ alkyl), —C(O)NR_(x)R_(x), C₃₋₆ cycloalkyl, ormorpholinyl; and Y, R₁, R₂, R_(2b), R_(2c), R₃, R₄, R₅, R_(x), m, and nare defined in the first aspect. Included in this embodiment arecompounds in which each R_(2a) is independently H, F, Cl, —CN,—NR_(x)R_(x), C₁₋₆ alkyl, C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl,—(CH₂)₀₋₂O(C₁₋₂ alkyl), —(CH₂)₀₋₂C(O)NR_(x)R_(x),—(CH₂)₁₋₃(cyclopropyl), —C(O)O(C₁₋₂ alkyl), —C(O)NR_(x)(C₁₋₃ alkyl),—CR_(x)═CH₂, —CH═CH(C₃₋₆ cycloalkyl), —C(O)(pyrrolidinyl), or a cyclicgroup selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, andpyrimidinyl, each substituted with zero, 1, or 2 R_(y); and each R_(y)is independently F, —CN, —CH₃, —CF₃, —OCH₃, —NHC(O)CH₃, —C(O)NH₂,—C(O)NH(CH₃), cyclopropyl, or morpholinyl. Also included in thisembodiment are compounds in which each R_(2a) is independently H, F, Cl,—CN, —NH₂, C₁₋₅ alkyl, —CF₃, —CH₂OH, —OCH₃, —CH₂OCH₃,—CH₂CH₂(cyclopropyl), —C(O)OCH₃, —C(O)N(CH₃)₂, —C(O)NH(CH₂CH₂CH₃),—CH═CH₂, —C(CH₃)═CH₂, —CH═CH(cyclopropyl), —C(O)(pyrrolidinyl), or acyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl,and pyrimidinyl, each substituted with zero, 1, or 2 R_(y); and eachR_(y) is independently F, —CN, —CH₃, —CF₃, —OCH₃, —NHC(O)CH₃, —C(O)NH₂,—C(O)NH(CH₃), cyclopropyl, or morpholinyl.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₃ is -L₁-A; and Y, R₁, R₂, R_(2a), R_(2b), R_(2c), R₄, R₅, L₁,A, m, and n are defined in the first aspect. Included in this embodimentare compounds in which each L₁ is a bond, —(CR_(x)R_(x))₁₋₂—,—(CR_(x)R_(x))₁₋₂O—, —CR_(x)R_(x)C(O)—,—(CR_(x)R_(x))₂NR_(x)(CR_(x)R_(x))₀₋₁—,—CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₀₋₄—, —C(O)(CR_(x)R_(x))₀₋₃—,—C(O)(CR_(x)R_(x))₀₋₂NR_(x)(CR_(x)R_(x))₀₋₂—,—C(O)(CR_(x)R_(x))₁₋₂C(O)NR_(x)—, —C(O)(CR_(x)R_(x))₀₋₁O—,—C(O)(CR_(x)R_(x))₁₋₂NHS(O)₂—, —C(O)NR_(x)(CR_(x)R_(x))₁₋₂—, or—S(O)₂(CR_(x)R_(x))₀₋₂—. Also included in this embodiment are compoundsin which L₁ is a bond, —(CR_(x)R_(x))₁₋₂—, —CR_(x)R_(x)C(O)—,—C(O)(CR_(x)R_(x))₀₋₁—, —C(O)O—, or —S(O)₂(CR_(x)R_(x))₀₋₂—.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₃ is -L₁-A; L₁ is a bond, —(CR_(x)R_(x))₁₋₂—,—CR_(x)R_(x)C(O)—, —C(O)(CR_(x)R_(x))₀₋₁—, —C(O)O—, or—S(O)₂(CR_(x)R_(x))₀₋₂—; A is azetidinyl, C₃₋₆ cycloalkyl,dioxotetrahydrothiophenyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,pyrazolidinonyl, pyrrolidinonyl, pyrrolidin-dionyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, or triazolyl,each substituted with zero, 1, or 2 R_(3a); and Y, R₁, R₂, R_(2a),R_(2b), R_(2c), R₄, R₅, m, and n are defined in the first aspect.Included in this embodiment are compounds in which R₁ is —CH(CH₃)₂. Alsoincluded in this embodiment are compounds in which Y is

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₃ is —CH₂(methyl triazolyl), —CH₂(trifluoromethyl phenyl),—CH₂(difluoromethyl, fluorophenyl), —CH₂(fluoro, chlorophenyl),—CH₂(difluorocyclopropyl), —CH₂CH₂(pyrrolidin-dionyl), —CH₂(oxetanyl),—CH₂(tetrahydropyranyl), —CH₂C(O)(hydroxypyrrolidinyl),—CH₂C(O)(pyrazolidinonyl), —CH₂C(O)(pyrrolidinyl), —CH₂(dimethylpyrazolyl), —CH₂(methyl pyrazolyl), —CH₂(pyrazolyl), —CH₂(cyclopropyl),—CH₂(tetrahydrofuranyl), —CH₂(i-propyl pyrazolyl), —CH₂(n-propylpyrazolyl), —CH(CH₃)(methyl pyrazolyl), —C(O)(aminocyclopropyl),—C(O)(hydroxypyrrolidinyl), —C(O)(methyl, hydroxypyrrolidinyl),—C(O)CH₂(pyrrolidinonyl), —C(O)CH₂(pyrrolidinyl), —C(O)O(methylpyrrolidinyl), —S(O)₂CH₂CH₂(pyrrolidinyl),—CH₂(hydroxytetrahydropyranyl), or a cyclic group selected fromcyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinonyl,tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, piperidinyl,and dioxotetrahydrothiophenyl, each substituted with zero, 1, or 2R_(3a); and Y, R₁, R₂, R_(2a), R_(2b), R_(2c), R_(3a), R₄, R₅, m, and nare defined in the first aspect. Included in this embodiment arecompounds in which each

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₃ is H, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃cyanoalkyl, —(CH₂)₀₋₄O(C₁₋₃ alkyl), —(CH₂CH₂O)₂₋₃O(C₁₋₃ alkyl),—CH₂CH₂NR_(x)R_(x), —CR_(x)R_(x)C(O)OH,—(CR_(x)R_(x))₀₋₂C(O)NR_(x)R_(x), —CH₂C(O)NR_(x)(C₁₋₃ alkyl),—CH₂C(O)NR_(x)(C₁₋₄ hydroxyalkyl), —(CR_(x)R_(x))₀₋₂S(O)₂(C₁₋₃ alkyl),—C(O)(C₁₋₃ alkyl), —C(O)(C₁₋₃ fluoroalkyl), —C(O)CR_(x)R_(x)NR_(x)R_(x),—C(O)(C₁₋₆ hydroxyalkyl), or —NR_(x)C(O)(C₁₋₃ alkyl); and R₁, R₂,R_(2a), R_(2b), R_(2c), R₄, R₅, R_(x), m, and n are defined in the firstaspect. Included in this embodiment are compounds in which each R_(3a)is independently F, Cl, —OH, —NH₂, C₁₋₃ alkyl, C₁₋₂ fluoroalkyl, or—C(O)NR_(x)R_(x). Also included are compounds in which each R_(3a) isindependently F, —OH, —CH₃, —CH(CH₃)₂, —CF₃, or —C(O)NH₂.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein each R₄ is independently F, —OH, —CH₃, or —OCH₃; or two R₄attached to the same carbon atom form ═O; and R₁, R₂, R_(2a), R_(2b),R_(2c), R₃, R₅, m, and n are defined in the first aspect. Included inthis embodiment are compounds in which each R₄ is independently F, —CH₃,or —OCH₃; or two R₄ attached to the same carbon atom form ═O.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein each R₅ is independently F, —CN, —CH₃, —CF₃, or —OCH₃; and R₁,R₂, R_(2a), R_(2b), R_(2c), R₃, R₄, m, and n are defined in the firstaspect. Included in this embodiment are compounds in which each R₅ isindependently F, —CH₃, or —CF₃. Also included in this embodiment arecompounds in which R₅ is F and n is zero or 1.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein Y is

R₁ is —CH(CH₃)₂; R₅ is F; m is zero; n is zero or 1; and R₂, R_(2a), R₃,and R₄ are defined in the first aspect. Included in this embodiment arecompounds in which n is zero.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is H, C₁₋₄ alkyl or C₁₋₃ fluoroalkyl, or C₃₋₆ cycloalkyl; R₂is C₁₋₄ alkyl, C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₃OCH₃, C₃₋₆cycloalkyl, —CH₂C(O)NR_(x)R_(x), —CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl),tetrahydrofuranyl, or phenyl; each R_(2a) is independently H, F, Cl,—CN, —NR_(x)R_(x), C₁₋₆ alkyl, C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl,—(CH₂)₀₋₂O(C₁₋₂ alkyl), —(CH₂)₀₋₂C(O)NR_(x)R_(x),—(CH₂)₁₋₃(cyclopropyl), —C(O)O(C₁₋₂ alkyl), —C(O)NR_(x)(C₁₋₃ alkyl),—CR_(x)═CH₂, —CH═CH(C₃₋₆ cycloalkyl), —C(O)(pyrrolidinyl), or a cyclicgroup selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, andpyrimidinyl, each substituted with zero, 1, or 2 R_(y); each R_(y) isindependently F, Cl, —CN, C₁₋₂ alkyl, C₁₋₂ alkoxy, —NR_(x)C(O)(C₁₋₂alkyl), —C(O)NR_(x)R_(x), C₃₋₆ cycloalkyl, or morpholinyl; R₃ is (a)-L₁-A; or (b) H, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃cyanoalkyl, —(CH₂)₀₋₃O(C₁₋₂ alkyl), —(CH₂CH₂O)₂₋₃O(C₁₋₂ alkyl),—CH₂CH₂NR_(x)R_(x), —CR_(x)R_(x)C(O)OH,—(CR_(x)R_(x))₀₋₂C(O)NR_(x)R_(x), —CH₂C(O)NR_(x)(C₁₋₂ alkyl),—CH₂C(O)NH(C₁₋₄ hydroxyalkyl), —(CR_(x)R_(x))₁₋₂S(O)₂(C₁₋₂ alkyl),—C(O)(C₁₋₂ alkyl), —C(O)(C₁₋₂ fluoroalkyl), —C(O)CR_(x)R_(x)NR_(x)R_(x),—C(O)(C₁₋₄ hydroxyalkyl), or —NR_(x)C(O)(C₁₋₂ alkyl); L₁ is a bond,—(CR_(x)R_(x))₁₋₂—, —CR_(x)R_(x)C(O)—, —C(O)(CR_(x)R_(x))₀₋₁—, —C(O)O—,or —S(O)₂(CR_(x)R_(x))₀₋₂—; A is azetidinyl, C₃₋₆ cycloalkyl,dioxotetrahydrothiophenyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,pyrazolidinonyl, pyrrolidinonyl, pyrrolidin-dionyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, or triazolyl,each substituted with zero, 1, or 2 R_(3a); each R_(3a) is independentlyF, Cl, —OH, —NH₂, C₁₋₃ alkyl, C₁₋₂ fluoroalkyl, or —C(O)NR_(x)R_(x);each R₄ is independently F, —OH, —CH₃, or —OCH₃; or two R₄ attached tothe same carbon atom form ═O; each R₅ is independently F, —CN, —CH₃,—CF₃, or —OCH₃; and R_(z) is H or —CH₃.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein R₁ is —CH₂CH₃ or —CH(CH₃)₂; R₂ is —CH₃, —CH₂CH₃, —CH(CH₃)₂,—CH₂CH(CH₃)₂, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂C(CH₃)₂OH, —CH₂CHF₂, —CH₂CF₃,—CH₂CH₂OCH₃, —CH₂(cyclopropyl), —CH₂(phenyl), —CH₂C(O)NH₂,tetrahydrofuranyl, or phenyl; each R_(2a) is independently H, F, Cl,—CN, —NH₂, C₁₋₅ alkyl, —CF₃, —CH₂OH, —OCH₃, —CH₂OCH₃,—CH₂CH₂(cyclopropyl), —C(O)OCH₃, —C(O)N(CH₃)₂, —C(O)NH(CH₂CH₂CH₃),—CH═CH₂, —C(CH₃)═CH₂, —CH═CH(cyclopropyl), —C(O)(pyrrolidinyl), or acyclic group selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl,and pyrimidinyl, each substituted with zero, 1, or 2 R_(y); each R_(y)is independently F, —CN, —CH₃, —CF₃, —OCH₃, —NHC(O)CH₃, —C(O)NH₂,—C(O)NH(CH₃), cyclopropyl, or morpholinyl; R_(2b) is R₂ or R_(2a);R_(2c) is R₂ or R_(2a); provided that one of R_(2b) and R_(2c) is R₂,and the other of R_(2b) and R_(2c) is R_(2a); R₃ is H, —CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CF₃,—CH₂CH₂CH₂CF₃, —CH₂CH₂CH(CF₃)₂, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —C(CH₃)₂OH,—CH₂C(CH₃)₂OH, —CH₂CH₂C(CH₃)₂OH, —CH₂CH(OH)CH(CH₃)₂, —CH₂CH(OH)CH₂OH,—CH(CH₂CH₂OH)₂, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃,—(CH₂CH₂O)₂₋₃OCH₃, —CH₂CH₂NH(CH₃), —C(CH₃)₂C(O)OH, —CH₂C(O)NH₂,—CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂, —CH₂C(O)NH(CH₂CH₃),—CH₂C(O)NH(CH₂CH(CH₃)OH), —CH₂C(O)NH(CH₂C(CH₃)₂OH), —CH(CH₃)C(O)NH₂,—C(CH₃)₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂CH₂S(O)₂CH₃, —C(O)CH₃, —C(O)CF₃,—C(O)CH₂N(CH₃)₂, —C(O)C(CH₃)₂NH₂, —C(O)CH(CH₃)NH(CH₃),—C(O)C(CH₃)₂NH(CH₃), —C(O)CH₂CH(CH₃)OH, —C(O)CH₂C(CH₃)₂OH,—C(O)C(CH₃)₂CH₂OH, —NHC(O)CH₃, —CH₂(methyl triazolyl),—CH₂(trifluoromethyl phenyl), —CH₂(difluoromethyl, fluorophenyl),—CH₂(fluoro, chlorophenyl), —CH₂(difluorocyclopropyl),—CH₂CH₂(pyrrolidin-dionyl), —CH₂(oxetanyl), —CH₂(tetrahydropyranyl),—CH₂C(O)(hydroxypyrrolidinyl), —CH₂C(O)(pyrazolidinonyl),—CH₂C(O)(pyrrolidinyl), —CH₂(dimethyl pyrazolyl), —CH₂(methylpyrazolyl), —CH₂(pyrazolyl), —CH₂(cyclopropyl), —CH₂(tetrahydrofuranyl),—CH₂(i-propyl pyrazolyl), —CH₂(n-propyl pyrazolyl), —CH(CH₃)(methylpyrazolyl), —C(O)(aminocyclopropyl), —C(O)(hydroxypyrrolidinyl),—C(O)(methyl, hydroxypyrrolidinyl), —C(O)CH₂(pyrrolidinonyl),—C(O)CH₂(pyrrolidinyl), —C(O)O(methyl pyrrolidinyl),—S(O)₂CH₂CH₂(pyrrolidinyl), —CH₂(hydroxytetrahydropyranyl), or a cyclicgroup selected from cyclopentyl, cyclohexyl, oxetanyl, azetidinyl,pyrrolidinonyl, tetrahydrofuranyl, tetrahydrofuranonyl,tetrahydropyranyl, piperidinyl, and dioxotetrahydrothiophenyl, eachsubstituted with zero, 1, or 2 R_(3a); each R_(3a) is independently F,—OH, —CH₃, —CH(CH₃)₂, —CF₃, or —C(O)NH₂; R₅ is F; m is zero; and n iszero or 1.

One embodiment provides a compound of Formula (I) or a salt thereof,wherein said compound is selected from5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-on(1);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(2);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(3);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,6-dimethylpyridin-2(1H)-one(6);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(8);3-amino-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(9);3-fluoro-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(13);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(14);1-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(15);1-isopropyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)pyridin-2(1H)-one(16);3-amino-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(19);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1-methylpyridin-2(1H)-one(20);3-chloro-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(22);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(23);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(24);3-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,6-dimethylpyridin-2(1H)-one(25);1-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3,4-dimethylpyridin-2(1H)-one(26);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1,6-dimethylpyridin-2(1H)-one(28);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1,4-dimethylpyridin-2(1H)-one(29);1-(2-hydroxyethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(30);3-chloro-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(31); 3-chloro-1-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)pyridin-2(1H)-one (32);3-chloro-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,6-dimethylpyridin-2(1H)-one(33);1-(cyclopropylmethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(34);1,3-diethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-6-methylpyridin-2(1H)-one(35);1-isobutyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(36); methyl5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate(37);1-(3-hydroxypropyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(38);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-(2-methoxyethyl)-3-methylpyridin-2(1H)-one(39);1-(2,2-difluoroethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(40);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(trifluoromethyl)pyridin-2(1H)-one(41);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methyl-1-(tetrahydrofuran-3-yl)pyridin-2(1H)-one(42);1-(2-hydroxy-2-methylpropyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(43);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methyl-1-phenylpyridin-2(1H)-one(44);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methyl-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one(45);1-benzyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(46);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(47);1-(2-hydroxy-2-methylpropyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)pyridin-2(1H)-one(48);2-(5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2-oxopyridin-1(2H)-yl)acetamide(49);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(50);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(prop-1-en-2-yl)pyridin-2(1H)-one(51);(E)-3-(2-cyclopropylvinyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(52);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-phenylpyridin-2(1H)-one(53);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(54);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(p-tolyl)pyridin-2(1H)-one (55);3-(5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzonitrile(56);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2′-methoxy-1-methyl[3,3′-bipyridin]-2(1H)-one(57);3-(5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzamide(58);3-(5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N-methylbenzamide(59);N-(3-(5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)acetamide(60);3-(3,3-dimethylbutyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(61);3-(2-cyclopropylethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(62);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-N,N,1-trimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide(63);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-N-propyl-1,2-dihydropyridine-3-carboxamide(64);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-[3,3′-bipyridin]-2(1H)-one(65);3-isopropyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(66);3-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(67);1,3-diethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)pyridin-2(1H)-one(68);-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrrolidine-1-carbonyl)pyridin-2(1H)-one (69);3-(hydroxymethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(70);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (71);5-(3-isopropyl-5-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(72);5-(5-(1-(3-hydroxy-3-methylbutyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(73);5-(5-(1-(3-hydroxy-3-methylbutyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(74);5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(75);3-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)propanenitrile(76); 5-(3-isopropyl-5-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(77);5-(5-(1-(5-(difluoromethoxy)-2-fluorobenzyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(78);5-(3-isopropyl-5-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(79);5-(5-(1-(5-chloro-2-fluorobenzyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(80);5-(5-(1-(1,1-dioxidotetrahydrothiophen-3-yl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(81);3-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)propanamide(82);5-(5-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(83);1-(2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)ethyl)pyrrolidine-2,5-dione(84);5-(5-(1-(3-hydroxypropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(85);5-(5-(1-isopentylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(86);5-(5-(1-cyclohexylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(87);5-(3-isopropyl-5-(1-(4,4,4-trifluoro-3-(trifluoromethyl)butyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(88);5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-3-phenylpyridin-2(1H)-one(89);5-(5-(1-isopentylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-3-phenylpyridin-2(1H)-one(90);3-chloro-5-(5-(1-isopentylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(91);3-chloro-5-(3-isopropyl-5-(1-(oxetan-3-ylmethyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(92);3-chloro-5-(3-isopropyl-5-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(93);5-(3-isopropyl-5-(1-(oxetan-3-ylmethyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(94);3-chloro-5-(3-isopropyl-5-(1-(2-methoxyethyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(95);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetonitrile(96);3-chloro-5-(5-(1-cyclopentylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(97); 3-chloro-5-(3-isopropyl-5-(1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one (98);3-chloro-5-(3-isopropyl-5-(1-(3-methoxypropyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(99);5-(3-isopropyl-5-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(100);3-chloro-5-(3-isopropyl-5-(1-(2-(2-methoxyethoxy)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(101); 3-chloro-5-(3-isopropyl-5-(1-(3,3,3-trifluoropropyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one (102);5-(3-isopropyl-5-(1-(2-methoxyethyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(103);5-(3-isopropyl-5-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(104);3-chloro-5-(3-isopropyl-5-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(105);3-chloro-5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(106); 3-chloro-5-(3-isopropyl-5-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one (107);5-(3-isopropyl-5-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one (108);5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-(2-methoxyethyl)-3-methylpyridin-2(1H)-one(109);1-isobutyl-5-(3-isopropyl-5-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(110);1-benzyl-5-(3-isopropyl-5-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(111);1-isobutyl-5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(112);1-benzyl-5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(113);2-(4-(3-isopropyl-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(114);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(117);(S)-5-(5-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(119); (R)-5-(5-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(120);5-(3-isopropyl-5-(1-(2-oxo-2-(3-oxopyrazolidin-1-yl)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(121); 5-(3-isopropyl-5-(1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one (122);(R)-5-(3-isopropyl-5-(1-(2-oxopyrrolidin-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(123);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-(2-hydroxy-2-methylpropyl)acetamide (124);(R)-2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-(2-hydroxypropyl)acetamide(125);(S)-2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-(2-hydroxypropyl)acetamide(126);5-(3-isopropyl-5-(1-(1-methyl-2-oxopyrrolidin-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(127);2-(4-(3-isopropyl-2-(5-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(128);2-(4-(3-isopropyl-2-(5-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide (129);2-(4-(2-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(132);2-(4-(2-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(133);2-(4-(3-isopropyl-2-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(134);2-(4-(3-isopropyl-2-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(135);2-(4-(2-(1-ethyl-4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(136);2-(4-(2-(1-ethyl-4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(137);2-(4-(3-isopropyl-2-(1,2,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(138);2-(4-(3-isopropyl-2-(1,2,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(139);2-(4-(3-isopropyl-2-(5-methoxy-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(140);2-(4-(3-isopropyl-2-(5-methoxy-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(141);2-(4-(3-isopropyl-2-(5-methoxy-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(142);2-(4-(3-isopropyl-2-(5-methoxy-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(143);2-(4-(2-(5-cyano-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(144);2-(4-(2-(5-cyano-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(145);2-(4-(2-(5-cyano-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(146);2-(4-(2-(5-cyano-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(147);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-2-methylpropanoicacid (148);5-(3-isopropyl-5-(1-(5-methyl-2-oxotetrahydrofuran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(149);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide(150);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-2-methylpropanamide(151);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(152);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(153);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-2-methylpropanamide(154);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-ethylacetamide(155);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)propanamide(156);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-ethyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (157);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(158);2-(4-(3-isopropyl-2-(1-(2-methoxyethyl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(159);2-(4-(3-isopropyl-2-(1-(2-methoxyethyl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(160);2-(4-(2-(1-isobutyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(161);2-(4-(2-(1-benzyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(162);2-(4-(2-(1-isobutyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(163);2-(4-(2-(1-benzyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(164);2-(4-(3-isopropyl-2-(5-methyl-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(165);2-(4-(2-(1-(2,2-difluoroethyl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(166);2-(4-(2-(1-(2-hydroxyethyl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(167);2-(4-(2-(5-ethyl-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(168);2-(4-(3-isopropyl-2-(1-methyl-2-oxo-1,2-dihydro-[3,3′-bipyridin]-5-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(169);2-(4-(3-isopropyl-2-(1-methyl-6-oxo-5-phenyl-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(170);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(171);5-(3-isopropyl-5-(1-(2-(methylamino)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(172);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(piperidin-1-yl)pyridin-2(1H)-one (173);5-(5-(1-(1-acetylazetidin-3-yl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-chloro-1,4-dimethylpyridin-2(1H)-one(174);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(175);5-(3-isopropyl-5-(1-(2-(methylamino)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(176);5-(3-isopropyl-5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(177); 5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one (178);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(179);5-(3-isopropyl-5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(180);5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(181);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(182);5-(3-isopropyl-5-(1-((1-methyl-1H-pyrazol-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(195);5-(3-isopropyl-5-(1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(196); 5-(3-isopropyl-5-(1-((1-methyl-1H-pyrazol-5-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(197);5-(3-isopropyl-5-(1-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(198);5-(5-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(199);5-(5-(1-((4H-pyrazol-3-yl)methyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(200);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1-methylpyridin-2(1H)-one(201);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1-methylpyridin-2(1H)-one(202);1-ethyl-5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(204);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(206);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(207);1-ethyl-5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3,4-dimethylpyridin-2(1H)-one(208);1-ethyl-5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-3,4-dimethylpyridin-2(1H)-one(209); 5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one (210);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(211);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(212);1-ethyl-5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-3,4-dimethylpyridin-2(1H)-one(213);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(214); 5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1,4-dimethylpyridin-2(1H)-one(215);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1,4-dimethylpyridin-2(1H)-one(216);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1,6-dimethylpyridin-2(1H)-one(217);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1,6-dimethylpyridin-2(1H)-one(218);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(219);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(220);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(221);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(222);5-(5-(1-(cyclopropylmethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(223);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(224);5-(3-isopropyl-5-(1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(225);3-chloro-5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(226);3-chloro-5-(3-isopropyl-5-(1-((1-isopropyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(227); 5-(3-isopropyl-5-(1-((1-propyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one (228);N-(4-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)cyclohexyl)acetamide (229);5-(3-isopropyl-5-(1-(4-(trifluoromethyl)cyclohexyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one (230);5-(3-isopropyl-5-(1-(4-(trifluoromethyl)cyclohexyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(231);5-(5-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(232);5-(3-isopropyl-5-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(233);5-(3-isopropyl-5-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(234);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(235);5-(5-(1-(2-hydroxyethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(236);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-[3,3′-bipyridin]-2(1H)-one(237);3-chloro-5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(238);3-chloro-5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(241);3-chloro-5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(240);5-(5-(1-acetylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-chloro-1,4-dimethylpyridin-2(1H)-one(241);3-chloro-5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(242);3-chloro-5-(5-(1-(1,5-dihydroxypentan-3-yl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(243);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(244);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(245);5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(246);5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(247);3-chloro-5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(248);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(249);3-chloro-5-(3-isopropyl-5-(1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(250);5-(5-(1-butylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-chloro-1,4-dimethylpyridin-2(1H)-one(251);3-chloro-5-(3-isopropyl-5-(1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(252);3-chloro-5-(5-(1-(2,3-dihydroxypropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(253);3-chloro-5-(3-isopropyl-5-(1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(254-255);5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(256);5-(3-isopropyl-5-(1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(257);5-(4-fluoro-3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(258);5-(4-fluoro-3-isopropyl-5-(1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(259);1-ethyl-5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-3-(pyrimidin-5-yl)pyridin-2(1H)-one(260);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1-(2-methoxyethyl)-3-methylpyridin-2(1H)-one(261);1-isobutyl-5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(262);1-benzyl-5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(263);1-(2-hydroxyethyl)-5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(264);5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-3-methyl-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one(265);1-(2,2-difluoroethyl)-5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(266);5-(5-(1-(4-(2-hydroxypropan-2-yl)cyclohexyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(267-268);5-(3-isopropyl-5-(1-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(269);5-(5-(1-(4-(2-hydroxypropan-2-yl)cyclohexyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(270);5-(5-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(271);5-(5-(1-(1-aminocyclopropanecarbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(272);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(273);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(274);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methoxy-1,6-dimethylpyridin-2(1H)-one(275);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methoxy-1,4-dimethylpyridin-2(1H)-one(276);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(277);3-chloro-5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(278);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(279);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(280); 5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-ethyl-3,4-dimethylpyridin-2(1H)-one(281);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-ethyl-3-methylpyridin-2(1H)-one(282);1-benzyl-5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(284); 5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-isobutyl-3-methylpyridin-2(1H)-one(285);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methoxy-1-methylpyridin-2(1H)-one(286);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-(2-methoxyethyl)-3-methylpyridin-2(1H)-one(287);5-(5-(1-((2R,4S)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(288);5-(5-(1-((2S,4R)-4-hydroxy-1-methylpyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(289);5-(5-(1-((2S,4R)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(290);5-(5-(1-((2S,3S)-3-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(291);5-(5-(1-((2R,4S)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(292);5-(5-(1-((2S,4R)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(293);5-(5-(1-(2-amino-2-methylpropanoyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(296);5-(3-isopropyl-5-(1-(methyl-L-alanyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(297);5-(3-isopropyl-5-(1-(2-methyl-2-(methylamino)propanoyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(298);5-(3-isopropyl-5-(1-(methyl-D-alanyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(299);5-(3-isopropyl-5-(1-(2-(2-oxopyrrolidin-1-yl)acetyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(300);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(301); 3-chloro-5-(3-isopropyl-5-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one (302);5-(5-(1-(3-hydroxy-3-methylbutanoyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(303);5-(5-(1-(3-hydroxy-2,2-dimethylpropanoyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(304); (S)-5-(5-(1-(3-hydroxybutanoyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(305);(R)-5-(3-isopropyl-5-(1-(2-(pyrrolidin-2-yl)acetyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(306);(S)-1-methylpyrrolidin-3-yl4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate(307); 3-chloro-5-(3-isopropyl-5-(1-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one (308);3-chloro-5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(309);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(310);5-(5-(1-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(313);5-(5-(1-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(314);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(315);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(316); 5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methoxy-1,4-dimethylpyridin-2(1H)-one(317);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methoxy-1,6-dimethylpyridin-2(1H)-one(318);5-(5-(1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(319);5-(5-(1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(320);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(321);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(322);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(323); 5-(5-(1-(2-hydroxy-3-methylbutyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(324);5-(5-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(325);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(326);3-chloro-5-(4-fluoro-5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(327);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-isobutyl-3-methylpyridin-2(1H)-one(328);1-benzyl-5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(329);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-6′-morpholino-[3,3′-bipyridin]-2(1H)-one(330);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-3-(2-methoxypyrimidin-5-yl)-1-methylpyridin-2(1H)-one(331);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1,5′-dimethyl-[3,3′-bipyridin]-2(1H)-one(332);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one(333);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (334);N-(5′-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1′-methyl-2′-oxo-1′,2′-dihydro-[3,3′-bipyridin]-6-yl)acetamide(335);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,4′-bipyridin]-2(1H)-one(336);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(2-methylpyrimidin-5-yl)pyridin-2(1H)-one(337);3-(2-cyclopropylpyrimidin-5-yl)-5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(338);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one (339);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-3-(3-methoxyphenyl)-1-methylpyridin-2(1H)-one(340);6′-fluoro-5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(341);6′-fluoro-5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(342);6′-fluoro-5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,5′-dimethyl-[3,3′-bipyridin]-2(1H)-one(343);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,2′-dimethyl-[3,3′-bipyridin]-2(1H)-one(244);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(345); 5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(346);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(347);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(348);5-(3-isopropyl-5-(1-(2-methoxyethyl)piperidin-4-yl)-1H-indol-2-yl)-1,6′-dimethyl-[3,3′-bipyridin]-2(1H)-one(349);5-(3-isopropyl-5-(1-(2-methoxyethyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one(350);2-(4-(3-isopropyl-2-(5-(methoxymethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(351);2-(4-(3-isopropyl-2-(1-methyl-6-oxo-5-vinyl-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(352); and5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(353).

One embodiment provides a compound of Formula (I) or a salt thereof,wherein said compound is selected from5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyrazin-2(1H)-one(4);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(12);2-(4-(2-(4,6-dimethyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(115);5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(183);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(184);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(185); 5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one (186);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(187);5-(3-isopropyl-5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(190);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(295); and5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(312).

One embodiment provides a compound of Formula (I) or a salt thereof,wherein said compound is selected from6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2-methylpyridazin-3(2H)-one(5);6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2,5-dimethylpyridazin-3(2H)-one(10);6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(11);6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2,4,5-trimethylpyridazin-3(2H)-one(17);2-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-4-methylpyridazin-3(2H)-one(18);2-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-4,5-dimethylpyridazin-3(2H)-one(27);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(116);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(118);2-(4-(3-isopropyl-2-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(130);2-(4-(3-isopropyl-2-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(131);6-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(188);6-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(189);6-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(191);6-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(192);6-(3-isopropyl-5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(193); 6-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one (194);6-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-2,4,5-trimethylpyridazin-3(2H)-one(203); 6-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-2,4,5-trimethylpyridazin-3(2H)-one (205);6-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-2,4,5-trimethylpyridazin-3(2H)-one(283); 6-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(294); and6-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(311).

One embodiment provides a compound of Formula (I) or a salt thereof,wherein said compound is5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione(21).

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. The inventionencompasses all combinations of the aspects and/or embodiments of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

Definitions

The features and advantages of the invention may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of theinvention that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof. Embodiments identified herein as exemplary or preferred areintended to be illustrative and not limiting.

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

As used herein, the phrase “compounds” refers to at least one compound.For example, a compound of Formula (I) includes a compound of Formula(I) and two or more compounds of Formula (I).

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference.

Listed below are definitions of various terms used to describe thepresent invention. These definitions apply to the terms as they are usedthroughout the specification (unless they are otherwise limited inspecific instances) either individually or as part of a larger group.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, andI.

The term “cyano” refers to the group —CN.

The term “amino” refers to the group —NH₂.

The term “oxo” refers to the group ═O.

The term “alkyl” as used herein, refers to both branched andstraight-chain saturated aliphatic hydrocarbon groups containing, forexample, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1to 4 carbon atoms. Examples of alkyl groups include, but are not limitedto, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl(e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl,3-methylpentyl, and 4-methylpentyl. When numbers appear in a subscriptafter the symbol “C”, the subscript defines with more specificity thenumber of carbon atoms that a particular group may contain. For example,“C₁₋₆ alkyl” denotes straight and branched chain alkyl groups with oneto six carbon atoms.

The term “fluoroalkyl” as used herein is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupssubstituted with one or more fluorine atoms. For example, “C₁₋₄fluoroalkyl” is intended to include C₁, C₂, C₃, and C₄ alkyl groupssubstituted with one or more fluorine atoms. Representative examples offluoroalkyl groups include, but are not limited to, —CF₃ and —CH₂CF₃.

The term “chloroalkyl” as used herein is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupssubstituted with one or more chlorine atoms. For example, “C₁₋₄chloroalkyl” is intended to include C₁, C₂, C₃, and C₄ alkyl groupssubstituted with one or more chlorine atoms. Representative examples offluoroalkyl groups include, but are not limited to, —CCl₃ and —CH₂CCl₃.

The term “cyanoalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more cyano groups. Forexample, “cyanoalkyl” includes —CH₂CN, —CH₂CH₂CN, and C₁₋₄ cyanoalkyl.

The term “aminoalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more amino groups. Forexample, “aminoalkyl” includes —CH₂NH₂, —CH₂CH₂NH₂, and C₁₋₄ aminoalkyl.

The term “hydroxyalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more hydroxyl groups. Forexample, “hydroxyalkyl” includes —CH₂OH, —CH₂CH₂OH, and C₁₋₄hydroxyalkyl.

The term “hydroxy-fluoroalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more hydroxyl groups andone or more fluorine atoms. For example, “hydroxy-fluoroalkyl” includes—CHFCH₂OH, —CH₂CHFC(CH₃)₂OH, and C₁₋₄ hydroxy-fluoroalkyl.

The term “cycloalkyl,” as used herein, refers to a group derived from anon-aromatic monocyclic or polycyclic hydrocarbon molecule by removal ofone hydrogen atom from a saturated ring carbon atom. Representativeexamples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in asubscript after the symbol “C”, the subscript defines with morespecificity the number of carbon atoms that a particular cycloalkylgroup may contain. For example, “C3-C6 cycloalkyl” denotes cycloalkylgroups with three to six carbon atoms.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom, for example, methoxygroup (—OCH₃). For example, “C₁₋₃ alkoxy” denotes alkoxy groups with oneto three carbon atoms.

The terms “fluoroalkoxy” and “—O(fluoroalkyl)” represent a fluoroalkylgroup as defined above attached through an oxygen linkage (—O—). Forexample, “C₁₋₄ fluoroalkoxy” is intended to include C₁, C₂, C₃, and C₄fluoroalkoxy groups.

The term “alkoxyalkoxy,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through an alkoxy group, forexample, methoxymethoxy group (—OCH₂OCH₃). For example, “C₁₋₄alkoxyalkoxy” denotes alkoxy groups with one to four carbon atoms.

The term “benzyl,” as used herein, refers to a methyl group in which oneof the hydrogen atoms is replaced by a phenyl group. The phenyl ring maybe unsubstituted or may contain one or more substituents as valenceallows.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The compounds of Formula (I) can be provided as amorphous solids orcrystalline solids. Lyophilization can be employed to provide thecompounds of Formula (I) as amorphous solids.

It should further be understood that solvates (e.g., hydrates) of thecompounds of Formula (I) are also within the scope of the presentinvention. The term “solvate” means a physical association of a compoundof Formula (I) with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates includehydrates, ethanolates, methanolates, isopropanolates, acetonitrilesolvates, and ethyl acetate solvates. Methods of solvation are known inthe art.

Various forms of prodrugs are well known in the art and are describedin:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch31, (Academic Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson andH. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers,1991); and

d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and JoachimM. Mayer, (Wiley-VCH, 2003).

In addition, compounds of Formula (I), subsequent to their preparation,can be isolated and purified to obtain a composition containing anamount by weight equal to or greater than 99% of a compound of Formula(I) (“substantially pure”), which is then used or formulated asdescribed herein. Such “substantially pure” compounds of Formula (I) arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to act as aninhibitor to TLR7/8/9, or effective to treat or prevent autoimmuneand/or inflammatory disease states, such as SLE, IBD, multiple sclerosis(MS), Sjögren's syndrome, and rheumatoid arthritis.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting its development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

The compounds of the present invention are intended to include allisotopes of atoms occurring in the present compounds. Isotopes includethose atoms having the same atomic number but different mass numbers. Byway of general example and without limitation, isotopes of hydrogeninclude deuterium (D) and tritium (T). Isotopes of carbon include ¹³Cand ¹⁴C. Isotopically-labeled compounds of the invention can generallybe prepared by conventional techniques known to those skilled in the artor by processes analogous to those described herein, using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed. For example, methyl (—CH₃) also includesdeuterated methyl groups such as —CD₃.

Utility

The human immune system has evolved to defend the body frommicro-organisms, viruses, and parasites that can cause infection,disease or death. Complex regulatory mechanisms ensure that the variouscellular components of the immune system target the foreign substancesor organisms, while not causing permanent or significant damage to theindividual. While the initiating events are not well understood at thistime, in autoimmune disease states the immune system directs itsinflammatory response to target organs in the afflicted individual.Different autoimmune diseases are typically characterized by thepredominate or initial target organ or tissues affected; such as thejoint in the case of rheumatoid arthritis, the thyroid gland in the caseof Hashimoto's thyroiditis, the central nervous system in the case ofmultiple sclerosis, the pancreas in the case of type I diabetes, and thebowel in the case of inflammatory bowel disease.

The compounds of the invention inhibit signaling through Toll-likereceptor 7, or 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof.Accordingly, compounds of Formula (I) have utility in treatingconditions associated with the inhibition of signaling through one ormore of TLR7, TLR8, or TLR9. Such conditions include TLR7, TLR8, or TLR9receptor associated diseases in which cytokine levels are modulated as aconsequence of intracellular signaling.

As used herein, the terms “treating” or “treatment” encompass thetreatment of a disease state in a mammal, particularly in a human, andinclude: (a) preventing or delaying the occurrence of the disease statein a mammal, in particular, when such mammal is predisposed to thedisease state but has not yet been diagnosed as having it; (b)inhibiting the disease state, i.e., arresting its development; and/or(c) achieving a full or partial reduction of the symptoms or diseasestate, and/or alleviating, ameliorating, lessening, or curing thedisease or disorder and/or its symptoms.

In view of their activity as selective inhibitors of TLR7, TLR8, orTLR9, the compounds of Formula (I) are useful in treating TLR7, TLR8, orTLR9 family receptor associated diseases, but not limited to,inflammatory diseases such as Crohn's disease, ulcerative colitis,asthma, graft versus host disease, allograft rejection, chronicobstructive pulmonary disease; autoimmune diseases such as Graves'disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis;auto-inflammatory diseases including CAPS, TRAPS, FMF, adult onsetStill's disease, systemic onset juvenile idiopathic arthritis, gout,gouty arthritis; metabolic diseases including type 2 diabetes,atherosclerosis, myocardial infarction; destructive bone disorders suchas bone resorption disease, osteoarthritis, osteoporosis, multiplemyeloma-related bone disorder; proliferative disorders such as acutemyelogenous leukemia, chronic myelogenous leukemia; angiogenic disorderssuch as angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; infectious diseases suchas sepsis, septic shock, and Shigellosis; neurodegenerative diseasessuch as Alzheimer's disease, Parkinson's disease, cerebral ischemias orneurodegenerative disease caused by traumatic injury, oncologic andviral diseases such as metastatic melanoma, Kaposi's sarcoma, multiplemyeloma, and HIV infection and CMV retinitis, AIDS, respectively.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic β-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoidosis, bone resorptiondisease, allograft rejections, fever and myalgias due to infection,cachexia secondary to infection, keloid formation, scar tissueformation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis, acute myelogenous leukemia, chronic myelogenousleukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma,sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson'sdisease, cerebral ischemias or neurodegenerative disease caused bytraumatic injury; angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; viral diseases includingacute hepatitis infection (including hepatitis A, hepatitis B andhepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy,and herpes; stroke, myocardial ischemia, ischemia in stroke heartattacks, organ hypoxia, vascular hyperplasia, cardiac and renalreperfusion injury, thrombosis, cardiac hypertrophy, thrombin-inducedplatelet aggregation, endotoxemia and/or toxic shock syndrome,conditions associated with prostaglandin endoperoxidase syndase-2, andpemphigus vulgaris. Preferred methods of treatment are those wherein thecondition is selected from Crohn's disease, ulcerative colitis,allograft rejection, rheumatoid arthritis, psoriasis, ankylosingspondylitis, psoriatic arthritis, and pemphigus vulgaris. Alternativelypreferred methods of treatment are those wherein the condition isselected from ischemia reperfusion injury, including cerebral ischemiareperfusions injury arising from stroke and cardiac ischemia reperfusioninjury arising from myocardial infarction. Another preferred method oftreatment is one in which the condition is multiple myeloma.

In one embodiment, the compounds of Formula (I) are useful in treatingcancer, including Waldenstrom's Macroglobulinemia (WM), diffuse large Bcell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), cutaneousdiffuse large B cell lymphoma, and primary CNS lymphoma.

In addition, the TLR7, TLR8, or TLR9 inhibitors of the present inventioninhibit the expression of inducible pro-inflammatory proteins such asprostaglandin endoperoxide synthase-2 (PGHS-2), also referred to ascyclooxygenase-2 (COX-2), IL-1, IL-6, IL-18, chemokines. Accordingly,additional TLR7/8/9 associated conditions include edema, analgesia,fever and pain, such as neuromuscular pain, headache, pain caused bycancer, dental pain and arthritis pain. The inventive compounds also maybe used to treat veterinary viral infections, such as lentivirusinfections, including, but not limited to equine infectious anemiavirus; or retrovirus infections, including feline immunodeficiencyvirus, bovine immunodeficiency virus, and canine immunodeficiency virus.

The present invention thus provides methods for treating suchconditions, comprising administering to a subject in need thereof atherapeutically-effective amount of at least one compound of Formula (I)or a salt thereof “Therapeutically effective amount” is intended toinclude an amount of a compound of the present invention that iseffective when administered alone or in combination to inhibitautoimmune disease or chronic inflammatory disease.

The methods of treating TLR7, TLR8, or TLR9 associated conditions maycomprise administering compounds of Formula (I) alone or in combinationwith each other and/or other suitable therapeutic agents useful intreating such conditions. Accordingly, “therapeutically effectiveamount” is also intended to include an amount of the combination ofcompounds claimed that is effective to inhibit TLR7, TLR8, or TLR9and/or treat diseases associated with TLR7, TLR8, or TLR9.

Exemplary of such other therapeutic agents include corticosteroids,rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs(CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide,and other immunosuppressants; nuclear translocation inhibitors, such asdeoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs)such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisoneor dexamethasone; antiviral agents such as abacavir; antiproliferativeagents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®);anti-malarials such as hydroxychloroquine; cytotoxic drugs such asazathiprine and cyclophosphamide; TNF-α inhibitors such as tenidap,anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus orRAPAMUNE®) or derivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds. The present invention alsoprovides pharmaceutical compositions capable of treating TLR7/8/9receptor-associated conditions, including IL-1 family receptor-mediateddiseases as described above.

The inventive compositions may contain other therapeutic agents asdescribed above and may be formulated, for example, by employingconventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (e.g., excipients, binders, preservatives, stabilizers,flavors, etc.) according to techniques such as those well known in theart of pharmaceutical formulation.

Accordingly, the present invention further includes compositionscomprising one or more compounds of Formula (I) and a pharmaceuticallyacceptable carrier.

A “pharmaceutically acceptable carrier” refers to media generallyaccepted in the art for the delivery of biologically active agents toanimals, in particular, mammals. Pharmaceutically acceptable carriersare formulated according to a number of factors well within the purviewof those of ordinary skill in the art. These include without limitationthe type and nature of the active agent being formulated; the subject towhich the agent-containing composition is to be administered; theintended route of administration of the composition; and, thetherapeutic indication being targeted. Pharmaceutically acceptablecarriers include both aqueous and non-aqueous liquid media, as well as avariety of solid and semi-solid dosage forms. Such carriers can includea number of different ingredients and additives in addition to theactive agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 17th Edition (1985), which is incorporated herein by referencein its entirety.

Compounds in accordance with Formula (I) can be administered by anymeans suitable for the condition to be treated, which can depend on theneed for site-specific treatment or quantity of Formula (I) compound tobe delivered.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising a compound of Formula (I) and one or morenon-toxic, pharmaceutically-acceptable carriers and/or diluents and/oradjuvants (collectively referred to herein as “carrier” materials) and,if desired, other active ingredients. The compounds of Formula (I) maybe administered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compounds and compositions ofthe present invention may, for example, be administered orally,mucosally, or parentally including intravascularly, intravenously,intraperitoneally, subcutaneously, intramuscularly, and intrasternallyin dosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. For example, thepharmaceutical carrier may contain a mixture of mannitol or lactose andmicrocrystalline cellulose. The mixture may contain additionalcomponents such as a lubricating agent, e.g. magnesium stearate and adisintegrating agent such as crospovidone. The carrier mixture may befilled into a gelatin capsule or compressed as a tablet. Thepharmaceutical composition may be administered as an oral dosage form oran infusion, for example.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, liquid capsule, suspension, orliquid. The pharmaceutical composition is preferably made in the form ofa dosage unit containing a particular amount of the active ingredient.For example, the pharmaceutical composition may be provided as a tabletor capsule comprising an amount of active ingredient in the range offrom about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, andmore preferably from about 0.5 to 100 mg. A suitable daily dose for ahuman or other mammal may vary widely depending on the condition of thepatient and other factors, but, can be determined using routine methods.

Any pharmaceutical composition contemplated herein can, for example, bedelivered orally via any acceptable and suitable oral preparations.Exemplary oral preparations, include, but are not limited to, forexample, tablets, troches, lozenges, aqueous and oily suspensions,dispersible powders or granules, emulsions, hard and soft capsules,liquid capsules, syrups, and elixirs. Pharmaceutical compositionsintended for oral administration can be prepared according to anymethods known in the art for manufacturing pharmaceutical compositionsintended for oral administration. In order to provide pharmaceuticallypalatable preparations, a pharmaceutical composition in accordance withthe invention can contain at least one agent selected from sweeteningagents, flavoring agents, coloring agents, demulcents, antioxidants, andpreserving agents.

A tablet can, for example, be prepared by admixing at least one compoundof Formula (I) with at least one non-toxic pharmaceutically acceptableexcipient suitable for the manufacture of tablets. Exemplary excipientsinclude, but are not limited to, for example, inert diluents, such as,for example, calcium carbonate, sodium carbonate, lactose, calciumphosphate, and sodium phosphate; granulating and disintegrating agents,such as, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, and alginic acid; binding agents, such as,for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; andlubricating agents, such as, for example, magnesium stearate, stearicacid, and talc. Additionally, a tablet can either be uncoated, or coatedby known techniques to either mask the bad taste of an unpleasanttasting drug, or delay disintegration and absorption of the activeingredient in the gastrointestinal tract thereby sustaining the effectsof the active ingredient for a longer period. Exemplary water solubletaste masking materials, include, but are not limited to,hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplarytime delay materials, include, but are not limited to, ethyl celluloseand cellulose acetate butyrate.

Hard gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one inert solid diluent, suchas, for example, calcium carbonate; calcium phosphate; and kaolin.

Soft gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one water soluble carrier,such as, for example, polyethylene glycol; and at least one oil medium,such as, for example, peanut oil, liquid paraffin, and olive oil.

An aqueous suspension can be prepared, for example, by admixing at leastone compound of Formula (I) with at least one excipient suitable for themanufacture of an aqueous suspension. Exemplary excipients suitable forthe manufacture of an aqueous suspension, include, but are not limitedto, for example, suspending agents, such as, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth,and gum acacia; dispersing or wetting agents, such as, for example, anaturally-occurring phosphatide, e.g., lecithin; condensation productsof alkylene oxide with fatty acids, such as, for example,polyoxyethylene stearate; condensation products of ethylene oxide withlong chain aliphatic alcohols, such as, for exampleheptadecaethylene-oxycetanol; condensation products of ethylene oxidewith partial esters derived from fatty acids and hexitol, such as, forexample, polyoxyethylene sorbitol monooleate; and condensation productsof ethylene oxide with partial esters derived from fatty acids andhexitol anhydrides, such as, for example, polyethylene sorbitanmonooleate. An aqueous suspension can also contain at least onepreservative, such as, for example, ethyl and n-propylp-hydroxybenzoate; at least one coloring agent; at least one flavoringagent; and/or at least one sweetening agent, including but not limitedto, for example, sucrose, saccharin, and aspartame.

Oily suspensions can, for example, be prepared by suspending at leastone compound of Formula (I) in either a vegetable oil, such as, forexample, arachis oil; olive oil; sesame oil; and coconut oil; or inmineral oil, such as, for example, liquid paraffin. An oily suspensioncan also contain at least one thickening agent, such as, for example,beeswax; hard paraffin; and cetyl alcohol. In order to provide apalatable oily suspension, at least one of the sweetening agents alreadydescribed hereinabove, and/or at least one flavoring agent can be addedto the oily suspension. An oily suspension can further contain at leastone preservative, including, but not limited to, for example, ananti-oxidant, such as, for example, butylated hydroxyanisol, andalpha-tocopherol.

Dispersible powders and granules can, for example, be prepared byadmixing at least one compound of Formula (I) with at least onedispersing and/or wetting agent; at least one suspending agent; and/orat least one preservative. Suitable dispersing agents, wetting agents,and suspending agents are as already described above. Exemplarypreservatives include, but are not limited to, for example,anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders andgranules can also contain at least one excipient, including, but notlimited to, for example, sweetening agents; flavoring agents; andcoloring agents.

An emulsion of at least one compound of Formula (I) thereof can, forexample, be prepared as an oil-in-water emulsion. The oily phase of theemulsions comprising compounds of Formula (I) may be constituted fromknown ingredients in a known manner. The oil phase can be provided by,but is not limited to, for example, a vegetable oil, such as, forexample, olive oil and arachis oil; a mineral oil, such as, for example,liquid paraffin; and mixtures thereof. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil. Suitableemulsifying agents include, but are not limited to, for example,naturally-occurring phosphatides, e.g., soy bean lecithin; esters orpartial esters derived from fatty acids and hexitol anhydrides, such as,for example, sorbitan monooleate; and condensation products of partialesters with ethylene oxide, such as, for example, polyoxyethylenesorbitan monooleate. Preferably, a hydrophilic emulsifier is includedtogether with a lipophilic emulsifier which acts as a stabilizer. It isalso preferred to include both an oil and a fat. Together, theemulsifier(s) with or without stabilizer(s) make-up the so-calledemulsifying wax, and the wax together with the oil and fat make up theso-called emulsifying ointment base which forms the oily dispersed phaseof the cream formulations. An emulsion can also contain a sweeteningagent, a flavoring agent, a preservative, and/or an antioxidant.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

The compounds of Formula (I) can, for example, also be deliveredintravenously, subcutaneously, and/or intramuscularly via anypharmaceutically acceptable and suitable injectable form. Exemplaryinjectable forms include, but are not limited to, for example, sterileaqueous solutions comprising acceptable vehicles and solvents, such as,for example, water, Ringer's solution, and isotonic sodium chloridesolution; sterile oil-in-water microemulsions; and aqueous or oleaginoussuspensions.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e.propylene glycol) or micellar solubilization (i.e. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

A sterile injectable oil-in-water microemulsion can, for example, beprepared by 1) dissolving at least one compound of Formula (I) in anoily phase, such as, for example, a mixture of soybean oil and lecithin;2) combining the Formula (I) containing oil phase with a water andglycerol mixture; and 3) processing the combination to form amicroemulsion.

A sterile aqueous or oleaginous suspension can be prepared in accordancewith methods already known in the art. For example, a sterile aqueoussolution or suspension can be prepared with a non-toxicparenterally-acceptable diluent or solvent, such as, for example,1,3-butane diol; and a sterile oleaginous suspension can be preparedwith a sterile non-toxic acceptable solvent or suspending medium, suchas, for example, sterile fixed oils, e.g., synthetic mono- ordiglycerides; and fatty acids, such as, for example, oleic acid.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that maybe used in the pharmaceutical compositions of this invention include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants usedin pharmaceutical dosage forms such as Tweens, polyethoxylated castoroil such as CREMOPHOR surfactant (BASF), or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin,or chemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals. The pharmaceutical compositions may be subjected toconventional pharmaceutical operations such as sterilization and/or maycontain conventional adjuvants, such as preservatives, stabilizers,wetting agents, emulsifiers, buffers etc. Tablets and pills canadditionally be prepared with enteric coatings. Such compositions mayalso comprise adjuvants, such as wetting, sweetening, flavoring, andperfuming agents.

The amounts of compounds that are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex, the medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.001 to 100 mg/kg body weight, preferably between about0.0025 and about 50 mg/kg body weight and most preferably between about0.005 to 10 mg/kg body weight, may be appropriate. The daily dose can beadministered in one to four doses per day. Other dosing schedulesinclude one dose per week and one dose per two day cycle.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered orally, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

Pharmaceutical compositions of this invention comprise at least onecompound of Formula (I) and optionally an additional agent selected fromany pharmaceutically acceptable carrier, adjuvant, and vehicle.Alternate compositions of this invention comprise a compound of theFormula (I) described herein, or a prodrug thereof, and apharmaceutically acceptable carrier, adjuvant, or vehicle.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a cardiovascular and/or inflammatorydisorder (as defined previously). In another embodiment, the packageinsert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat cardiovascular and/or inflammatory disorder. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Methods of Preparation

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety by reference.

The compounds of this invention may be prepared using the reactions andtechniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used. This will sometimes requirea judgment to modify the order of the synthetic steps or to select oneparticular process scheme over another in order to obtain a desiredcompound of the invention. It will also be recognized that another majorconsideration in the planning of any synthetic route in this field isthe judicious choice of the protecting group used for protection of thereactive functional groups present in the compounds described in thisinvention. An authoritative account describing the many alternatives tothe trained practitioner is Greene and Wuts (Protective Groups InOrganic Synthesis, Third Edition, Wiley and Sons, 1999).

Compounds of Formula (I) may be prepared by reference to the methodsillustrated in the following Scheme. As shown therein the end product isa compound having the same structural formula as Formula (I). It will beunderstood that any compound of Formula (I) may be produced by theschemes by the suitable selection of reagents with appropriatesubstitution. Solvents, temperatures, pressures, and other reactionconditions may readily be selected by one of ordinary skill in the art.Starting materials are commercially available or readily prepared by oneof ordinary skill in the art. Constituents of compounds are as definedherein or elsewhere in the specification.

As shown in Scheme 1, compounds of Formula I may be produced, startingwith the substituted 5-haloindoles (2). 2 can be prepared from the3-formyl indoles (via reduction) or from the 3-H indoles, viaalkylation. Transition metal catalyzed cross coupling of 2 and boronate3 followed by olefin reduction and bromination affords 4, which can thenbe converted to the boronic ester 5. Transition metal catalyzed crosscoupling of 5 with aryl halide 6 followed by Boc deprotection yields 7.Alkylation of 7 leads to the production of the compounds of Formula I.

Abbreviations

-   Ac acetyl-   ACN acetonitrile-   anhyd. anhydrous-   aq. aqueous-   BH₃DMS boron dimethylsulfide-   Bn benzyl-   Bu butyl-   Boc tert-butoxycarbonyl-   CV Column Volumes-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE dichloroethane-   DCM dichloromethane-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   EtOAc ethyl acetate-   Et ethyl-   EtOH ethanol-   Et₃N triethylamine-   H or H₂ hydrogen-   h, hr or hrs hour(s)-   hex hexane-   i iso-   IPA isopropyl alcohol-   HCl hydrochloric acid-   HPLC high pressure liquid chromatography-   LC liquid chromatography-   M molar-   mM millimolar-   Me methyl-   MeOH methanol-   MHz megahertz-   min. minute(s)-   mins minute(s)-   M⁺¹ (M+H)⁺-   MS mass spectrometry-   n or N normal-   NBS n-bromosuccinimide-   nm nanometer-   nM nanomolar-   Pd/C palladium on carbon-   PdCl₂(dppf)    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Ph phenyl-   Pr propyl-   PSI pounds per square inch-   Ret Time retention time-   sat. saturated-   SFC supercritical fluid chromatography-   T3P propane phosphonic anhydride-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TsCl 4-toluenesulfonyl chloride-   XPhos G2 Precatalyst    chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

Analytical and Preparative HPLC Conditions:

-   QC-ACN-AA-XB: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm    particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM    ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM    ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3    minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min;    Detection: UV at 220 nm.-   QC-ACN-TFA-XB: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm,    1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%    trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with    0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B    over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min;    Detection: UV at 220 nm.-   Method A1: L3 Acquity: Column: (LCMS) UPLC BEH C18, 2.1×50 mm, 1.7    μm particles; Mobile Phase: (A) water; (B) acetonitrile; Buffer:    0.05% TFA; Gradient Range: 2%-98% B (0 to 1 min) 98% B (to 1.5 min)    98%-2% B (to 1.6 min); Gradient Time: 1.6 min; Flow Rate: 0.8    mL/min; Analysis Time: 2.2 min; Detection: Detector 1: UV at 220 nm;    Detector 2: MS (ESI⁺).-   Method B1: L2 Aquity(4); Column: (LCMS) UPLC BEH C18, 2.1×50 mm, 1.7    μm particles; Mobile Phase: (A) water; (B) acetonitrile; Buffer:    0.05% TFA; Gradient Range: 2%-98% B (0 to 1 min) 98% B (to 1.5 min)    98%-2% B (to 1.5 min); Gradient Time: 1.8 min; Flow Rate: 0.8    mL/min; Analysis Time: 2.2 min; Detection: Detector 1: UV at 220 nm;    Detector 2: MS (ESI⁺).-   Method C1 SCP: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm,    1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM    ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM    ammonium acetate. Temperature: 50° C.; Gradient: 0-100% B over 3    minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min;    Detection: UV at 220 nm.-   Method D1 SCP: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm,    1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%    trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with    0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B    over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11    mL/min; Detection: UV at 220 nm.-   Method D2 SCP: Column: XBridge C18, 19×200 mm, 5-μm particles;    Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium    acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM    ammonium acetate; Gradient: 10-50% B over 20 minutes, then a    5-minute hold at 100% B; Flow: 20 mL/min. Detection: UV at 220 nm.-   Method D3 SCP: Column: XBridge C18, 19×200 mm, 5-μm particles;    Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic    acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1%    trifluoroacetic acid; Gradient: 6-46% B over 20 minutes, then a    4-minute hold at 100% B; Flow: 20 mL/min. Detection: UV at 220 nm.-   Method E1 iPAC: Column: Waters Xbridge C18 4.6×50 mm 5 um particles;    Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;    Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate.    Temperature: 50° C.; Gradient: 0-100% B over 1 minute; Flow: 4    mL/min; Detection: UV at 220 nm.-   Method F1 iPAC: Column: Waters Acquity BEH C18 2.1×50 mm 1.7-μm    particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%    trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with    0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B    over 2.20 minutes; Flow: 0.800 mL/min; Detection: UV at 220 nm.-   Waters Acquity SDS: Run Time: 2.20 min; Comment: Generic gradient;    Solvent Selection A: A1; Solvent Selection B: B1; Low Pressure    Limit: 0 psi; High Pressure Limit: 15000 psi; Solvent Name A: 100%    H₂O w/0.05% TFA; Solvent Name B: 100% ACN w/0.05% TFA.-   (A): Column-Ascentis Express C18 (50×2.1 mm-2.7 μm) Mphase A: 10 mM    NH₄COOH in water: ACN (98:02); Mphase B: 10 mM NH₄COOH in water: ACN    (02:98), Gradient: 0-100% B over 3 minutes, Flow=1 mL/min.-   (B): Waters Acquity BEH C18 (2.1×50 mm) 1.7 micron; Buffer: 5 mM    ammonium acetate pH 5 adjusted with HCOOH, Solvent A: Buffer:ACN    (95:5), Solvent B: Buffer:ACN (5:95), Method:% B: 0 min-5%: 1.1 min    -95%: 1.7 min-95%, Flow: 0.8 mL/min.-   (C): Column-Ascentis Express C18 (50×2.1 mm-2.7 μm) Mobile phase A:    0.1% HCOOH in water; Mobile phase B: ACN. Temperature: 50° C.;    Gradient: 0-100% B over 3 minutes; Flow rate: 1.0 mL/min.-   (D): Kinetex XB-C18 (75×3 mm) 2.6 micron; Solvent A: 10 mM ammonium    formate in water: acetonitrile (98:02); Mobile Phase B: 10 mM    ammonium formate in water: acetonitrile (02:98); Temperature: 50°    C.; Gradient: 0-100% B over 3 minutes; Flow rate: 1.1 mL/min;    Detection: UV at 220 nm.-   (E): Column: Ascentis Express C18 (50×2.1)mm, 2.7 μm; Mobile Phase    A: 5:95 acetonitrile: water with 10 mM NH₄OAc; Mobile Phase B: 95:5    acetonitrile: water with 10 mM NH₄OAc; Temperature: 50° C.;    Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min.-   (F): Column: Ascentis Express C18 (50×2.1)mm, 2.7 μm; Mobile Phase    A: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B: 95:5    acetonitrile: water with 0.1% TFA; Temperature: 50° C.; Gradient:    0-100% B over 3 minutes; Flow: 1.1 mL/min.-   (G): Column: Waters Acquity UPLC BEH C18 (2.1×50 mm), 1.7 micron;    Solvent A=100% water with 0.05% TFA; Solvent B=100% acetonitrile    with 0.05% TFA; gradient=2-98% B over 1 minute, then a 0.5-minute    hold at 98% B; Flow rate: 0.8 mL/min; Detection: UV at 220 nm.

Template 1: tert-butyl4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate

Intermediate T-1A: 5-bromo-3-isopropyl-1H-indole

A 250 mL round bottom flask was charged with triethylsilane (8.90 g, 77mmol), trichloroacetic acid (6.25 g, 38.3 mmol) and toluene (50 mL). Thesolution was heated to 70° C., then a solution of 5-bromo-1H-indole (5.0g, 25.5 mmol) and acetone (2.247 mL, 30.6 mmol) in toluene (30 mL) wasadded drop wise via an addition funnel. The resulting brown solution washeated at 70° C. for 1.5 h. The solution was cooled to 10° C., quenchedwith 10% sodium bicarbonate and diluted with diethyl ether. The organiclayer was separated, dried, and concentrated under vacuum to affordcrude compound. The crude was purified using silica gel chromatographyeluting with 5% ethyl acetate in hexanes to afford5-bromo-3-isopropyl-1H-indole (5.5 g, 23.10 mmol 95% yield) as an oil.LC retention time 1.42 min [D]. MS (E−) m/z: 238.2 (M+H). ¹H NMR (400MHz, DMSO-d₆) δ 10.96 (br s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.31 (d, J=8.6Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 7.15 (t, J=2.1 Hz, 1H), 3.12 (dtd,J=13.8, 6.8, 0.7 Hz, 1H), 1.29 (d, J=6.8 Hz, 6H).

Intermediate T-1B: tert-butyl4-(3-isopropyl-1H-indol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a mixture of 5-bromo-3-isopropyl-1H-indole (5.5 g, 23.10 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(7.50 g, 24.25 mmol) in a 250 mL round bottom flask were added THF (50mL) followed by aqueous solution of potassium phosphate, dibasic (12.07g, 69.3 mmol, 20 mL). The resulting reaction mixture was degassed for 10minutes with nitrogen gas, then PdCl₂(dppf)-CH₂Cl₂ adduct, (0.472 g,0.577 mmol) was added. The mixture was degassed again for 5 min. Theresulting reaction mixture was heated at 75° C. for 18 hours. Thereaction mixture was diluted with ethyl acetate (100 mL), poured into aseparate funnel and was washed with water (2×50 mL), brine (50 mL),dried over sodium sulfate, and concentrated to afford crude product. Thecrude material was purified using silica gel chromatography, elutingwith 15% ethyl acetate in hexane. The fractions were collected andconcentrated to afford tert-butyl443-isopropyl-1H-indol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (6.5g, 83% yield) as an oil. LCMS retention time 1.21 min [B]. MS (E−) m/z:339 (M−H). ¹H NMR (400 MHz, CHLOROFORM-d) 7.94 (br. s., 1H), 7.67-7.61(m, 1H), 7.33 (dd, 0.5 Hz, 1H), 7.27 (dd, J=8.6, 1.7 Hz, 1H), 6.98 (dd,J=2.3, 0.7 Hz, 1H), 6.02 (br. s., 1H), 4.12 (d, J=2.0 Hz, 2H), 3.70 (t,J=5.7 Hz, 2H), 3.24 (sptd, J=6.8, 0.7 Hz, 1H), 2.66 (br. s., 2H), 1.53(s, 9H), 1.39 (d, J=6.8 Hz, 6H).

Intermediate T-1C: tert-butyl4-(3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(3-isopropyl-1H-indol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (7.9g, 23.20 mmol) in ethyl acetate (150 mL), under a nitrogen atmosphere,was added palladium on carbon (0.617 g, 0.580 mmol). The vessel waspimp/purged three times with nitrogen gas then evacuated. Hydrogen gaswas introduced via a balloon and the mixture was stirred at roomtemperature for 5 hours. The suspension was filtered through celite andthe filtrate was concentrated to afford crude compound. The cruderesidue was purified by ISCO using a 40 g silica column, eluting with15% ethyl acetate in hexane. The combined fractions were collected andconcentrated to afford tert-butyl4(3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (6.5 g, 82% yield)as a white solid. LCMS retention time 2.48 min [C]. MS (E−) m/z: 341(M−H). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.88 (br. s., 1H), 7.48 (s, 1H),7.31 (d, J=8.3 Hz, 1H), 7.06 (dd, J=8.3, 1.6 Hz, 1H), 6.97 (d, J=1.8 Hz,1H), 4.29 (br. s., 2H), 3.22 (sptd, J=6.8, 0.5 Hz, 1H), 2.86 (t, J=12.3Hz, 2H), 2.77 (tt, J=12.1, 3.7 Hz, 1H), 1.91 (d, J=13.0 Hz, 2H), 1.73(qd, J=12.8, 4.6 Hz, 2H), 1.52 (s, 9H), 1.38 (d, J=7.0 Hz, 6H).

Template 1: tert-butyl4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl4(3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (6.3 g, 18.40 mmol)in DCE (60 mL) was added NBS (3.27 g, 18.40 mmol) dissolved in DCE (50mL) drop wise via an addition funnel over 10 min at 0° C. The resultingbrown solution was stirred at room temperature for 20 min. The reactionwas quenched with sodium sulfite solution (15 mL). The volatiles wereremoved and the residue was taken up in DCM (50 mL) and the aqueouslayer was separated. The organic layer was dried over Na₂SO₄ andconcentrated to afford crude compound. The crude material was purifiedby ISCO using 40 g silica column. The compound eluted in 15% ethylacetate in petroleum ether, the fractions were collected andconcentrated to afford tert-butyl4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (6.4 g,83% yield) as a white solid. LCMS retention time 2.58 min [H]. MS (E⁻)m/z: 367.2 (M−H). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.88 (br. s., 1H),7.48 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.06 (dd, J=8.3, 1.6 Hz, 1H), 6.97(d, J=1.8 Hz, 1H), 4.29 (br. s., 2H), 3.22 (sptd, J=6.8, 0.5 Hz, 1H),2.86 (t, J=12.3 Hz, 2H), 2.77 (tt, J=12.1, 3.7 Hz, 1H), 1.91 (d, J=13.0Hz, 2H), 1.73 (qd, J=12.8, 4.6 Hz, 2H), 1.52 (s, 9H), 1.38 (d, J=7.0 Hz,6H).

Template 2: tert-butyl4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate

To a mixture of tert-butyl4-(2-bromo-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (1.0 g,2.373 mmol), 2-dicyclohexyphosphino-2′,6′-dimethoxybiphenyl (0.117 g,0.285 mmol) and bis(benzonitrile)palladium(II)chloride (0.027 g, 0.071mmol) in a 50 mL reaction tube was added dioxane (10 mL). The resultingreaction mixture was degassed for 10 min and then pinacolborane (0.456g, 3.56 mmol) was added followed by dropwise addition of TEA (0.992 mL,7.12 mmol). The solution was again degassed for 5 min. The resultingreaction mixture was heated at 85° C. for 3 h. The reaction mixture wasconcentrated and the crude residue was dissolved in ethyl acetate (100mL), poured into a separatory funnel and was washed thoroughly withwater (2×250 mL). The organic layer was dried over Na₂SO₄, filtered andthe filtrate was concentrated under vacuum to afford the crude product.The residue was taken up in DCM (3 mL) .The crude was purified bycombiflash system by eluting with 12% EtOAc/Pet ether. Followingconcentration of the fractions, the product was isolated as a whitegummy product (0.75 g, 67.5% yield). LCMS retention time 4.27 min [H].MS (E−) m/z: 467.3(M−H). ¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1H), 7.50(s, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.99 (dd, J=8.5, 1.3 Hz, 1H), 4.09 (brd, J=11.1 Hz, 2H), 3.71-3.61 (m, 1H), 2.91-2.66 (m, 3H), 1.77 (br d,J=11.7 Hz, 2H), 1.59-1.46 (m, 2H), 1.43 (s, 9H), 1.36 (d, J=7.1 Hz, 6H),1.32 (s, 12H).

Template 3: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-1H-indole-1-carboxylate

Tert-butyl 4-(3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (328mg, 0.958 mmol) (T-1C) was dissolved in THF (7662 μl) in a 50 mLrecovery flask containing a Teflon-covered stir bar. Di-tert-butyldicarbonate (298 μl, 1.245 mmol) was added to the flask, followed by4-dimethylaminopyridine (11.70 mg, 0.096 mmol). The flask was capped andstirred at room temperature for 16 h. Excess solvent was evaporated fromthe reaction mixture under reduced pressure. The residue was taken up inDCM (˜3 mL) and purified by flash chromatography on a 24 g SiO₂ column,eluting with 0%-50% gradient using EtOAc and hexanes, on an ISCO Rfinstrument to afford tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-1H-indole-1-carboxylate(313.7 mg, 0.702 mmol, 73.3% yield) as a colorless foam. LCMS ofproduct; mass ion observed corresponds to (product−2×tBu)=331.3, 1.51min). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.05 (d, J=6.2 Hz, 1H), 7.39 (d,J=1.6 Hz, 1H), 7.33 (br. s., 1H), 7.17 (dd, J=8.6, 1.7 Hz, 1H), 4.29(br. s., 2H), 3.13 (sptd, J=6.8, 0.9 Hz, 1H), 2.86 (t, J=12.3 Hz, 2H),2.77 (tt, J=12.0, 3.5 Hz, 1H), 1.90 (d, J=12.7 Hz, 2H), 1.80-1.70 (m,2H), 1.68 (s, 9H), 1.52 (s, 9H), 1.36 (d, J=7.0 Hz, 6H).

Tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-1H-indole-1-carboxylate(100 mg, 0.226 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (73.8 μl, 0.362mmol) were dissolved in THF (1808 μl) in a 2-dram vial containing aTeflon-covered stir bar. The vial was cooled to −20° C. (dry ice/NMPbath) under an N₂ atmosphere. Lithium diisopropylamide (169 μl, 0.339mmol) was added dropwise to the vial (via a syringe through the septumcap) over ˜15 min. The reaction mixture was stirred at −20° C. for 1 h,then allowed to slowly warm to 10° C. The reaction was quenched byaddition of 1 M KHSO₄ (2 mL), and the resulting mixture was extractedwith EtOAc (3×2 mL). The combined organic exacts were dried over Na₂SO₄,and filtered. Excess solvent was evaporated off under an N₂ stream. Theresidue was taken up in DCM (2.5 mL) and purified by flashchromatography on a 4 g SiO₂ column, eluting with 0%-50% gradient usingEtOAc and hexanes, on an ISCO Rf instrument to afford tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(112.9 mg, 0.189 mmol, 83% yield) as a colorless foam, m/z, (observedM−2tBu+H⁺=457.2, M+H⁺=569.3). A mass ion corresponding to the startingmaterial was not observed. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.79 (d,J=8.6 Hz, 1H), 7.42 (d, J=1.5 Hz, 1H), 7.09 (dd, J=8.6, 1.6 Hz, 1H),4.28 (br. s., 2H), 3.20 (spt, J=7.1 Hz, 1H), 2.85 (t, J=12.2 Hz, 2H),2.74 (tt, J=12.1, 3.5 Hz, 1H), 1.89 (d, J=12.7 Hz, 2H), 1.75-1.69 (m,2H), 1.68 (s, 9H), 1.51 (s, 9H), 1.44 (s, 12H), 1.42 (d, J=7.1 Hz, 6H).

Fragment 1: 5-bromo-1,3-dimethylpyridin-2(1H)-one

To a mixture containing 5-bromo-3-methylpyridin-2(1H)-one (1.3 g, 6.91mmol) and K₂CO₃ (2.87 g, 20.74 mmol) in DMF (20 mL) was added dropwiseMeI (0.865 mL, 13.83 mmol). The reaction mixture was stirred for 16 hand diluted with ethyl acetate (150 mL). The mixture was filteredthrough a pad of celite to remove the solids and the filtrate was washedwith aqueous 10% LiCl solution (3×30 mL). The aqueous washes werecombined and back extracted with additional ethyl acetate (2×25 mL). Theorganic extracts were combined and washed with saturated aqueous NaClsolution (50 mL), dried (Na₂SO₄), filtered and concentrated to afford amixture of O-methylated (minor) and N-methylated (major) products. Thecrude product was dissolved in a small amount of DCM and charged to a 24g ISCO silica gel column which was eluted over a 15 min gradient with10%-100% hexanes/ethyl acetate to afford5-bromo-1,3-dimethylpyridin-2(1H)-one (1 g, 4.95 mmol, 71.6% yield).LCMS MH⁺: 202. HPLC Ret. Time 0.64 min. Method: Method B1. ¹H NMR: (400MHz, CHLOROFORM-d) δ 7.32 (d, J=2.6 Hz, 1H), 7.30-7.25 (J=2.6 Hz, 1H),3.55 (s, 3H), 2.17 (s, 3H).

Fragment 2: 5-bromo-1-isobutyl-3-methylpyridin-2(1H)-one

To a 20 mL vial with a pressure relief septum containing5-bromo-3-methylpyridin-2(1H)-one (250 mg, 1.330 mmol) were added DMF(2.659 mL), potassium carbonate (184 mg, 1.330 mmol) and1-bromo-2-methylpropane (182 mg, 1.330 mmol). The vial was sealed. Thereaction mixture was stirred at 65° C. for 4 hours, and then at roomtemperature overnight. The contents of the vial were diluted with brine(20 mL) and extracted with ethyl acetate (3×25 mL). The combined organicextracts were washed with water (10 mL), dried over sodium sulfate,filtered and concentrated to yield an oil. The oil was purified on anIsco silica gel column (24 g) eluting with 100% hexane to 100% ethylacetate over 15 minutes. Like fractions were combined and concentratedunder vacuum to afford 5-bromo-1-isobutyl-3-methylpyridin-2(1H)-one (175mg, 0.717 mmol, 53.9% yield). LCMS MH⁺: 244. HPLC Ret. Time 0.85 min.Method: Method B1.

Fragment 3: 5-Bromo-3-methyl-1-phenylpyridin-2(1H)-one

To a dried nitrogen flushed 50 mL round bottom flask containing 3 Åmolecular sieves (100 mg) were added 5-bromo-3-methylpyridin-2(1H)-one(100 mg, 0.532 mmol), phenylboronic acid (46.3 mg, 0.380 mmol), copper(II) acetate (207 mg, 1.140 mmol), pyridine (92 μl, 1.140 mmol), andpyridine-N-oxide (108 mg, 1.140 mmol) in DCM (5427 μl). Air (passed overdrying agent) was bubbled into the solution for 15 minutes. The flaskwas sealed and the reaction mixture was stirred at room temperature for3 days. The solution was filtered, washed with brine (2×10 mL), driedover sodium sulfate, filtered and concentrated under vacuum. Theresulting solid was purified on an Isco silica gel column (12 g, 100%hexanes-100% EtOAc). Fractions were combined and concentrated undervacuum to afford 5-bromo-3-methyl-1-phenylpyridin-2(1H)-one (10 mg,0.038 mmol, 9.97% yield). LCMS MH⁺: 266. HPLC Ret. Time 0.83 min. MethodB1.

Fragment 4: 5-Bromo-1,3,4-trimethylpyridin-2(1H)-one

To a mixture of 5-bromo-3,4-dimethylpyridin-2-amine (0.6 g, 2.98 mmol)in concentrated H₂SO₄ (2 mL) and water (15 mL) was added a solution ofsodium nitrite (0.309 g, 4.48 mmol) in water (1.5 mL) at 0° C. Themixture was allowed to equilibrate to room temperature and stirred for 1h. The precipitate was filtered and washed with water and dried toafford 5-bromo-3,4-dimethylpyridin-2-ol (400 mg, 1.980 mmol, 66.3%yield). m/z (203, M+H).

To a mixture containing 5-bromo-3,4-dimethylpyridin-2-ol (500 mg, 2.475mmol) and K₂CO₃ (684 mg, 4.95 mmol) in DMF (5 mL) was added MeI (0.309mL, 4.95 mmol). The reaction mixture was stirred for 20 h. The reactionmixture was diluted with ethyl acetate (100 mL) and the solids werefiltered through a pad of celite. The filtrate was washed with aqueous10% LiCl solution (3×20 mL). The aqueous washes were combined and backextracted with ethyl acetate (2×25 mL). The organic extracts werecombined and washed with saturated aqueous NaCl solution (50 mL), dried(Na₂SO₄), filtered and concentrated to afford a mixture of O-methylated(minor) and N-methylated products.

The crude product was dissolved in a small amount of DCM and charged toa 12 g ISCO silica gel column which was eluted over a 15 min gradientwith 10%-100% hexanes/ethyl acetate to afford5-bromo-1,3,4-trimethylpyridin-2(1H)-one (430 mg, 1.990 mmol, 80%yield), m/z (218, M+H). LCMS MH⁺: 218. HPLC Ret. Time 0.70 min. MethodB1. ¹H NMR : (400 MHz, CHLOROFORM-d) δ 7.39 (s, 1H), 3.54 (s, 3H), 2.29(s, 3H), 2.21 (s, 3H).

Fragment 5: 5-bromo-3-chloro-1,6-dimethylpyridin-2(1H)-one

A solution containing 5-bromo-6-methylpyridin-2-ol (1 g, 5.32 mmol) andNCS (0.852 g, 6.38 mmol) in THF (20 mL) was heated at 60° C. for 2 h.Additional NCS (˜100 mg) was added and the reaction mixture was heatedfor an additional 1 h, cooled to room temperature and concentrated todryness. The residue was re-suspended in diethyl ether/hexanes (20 mL,9/1), stirred and sonicated for 1 h. The solids were collected andrinsed with additional ether/hexanes mixture (20 mL, 9/1). The filtratewas re-concentrated ˜½ volume to afford second crop of5-bromo-3-chloro-6-methylpyridin-2-ol (1 g total), m/z (224, M+H). Theproduct was contaminated with ˜10% of a bis chlorinated material, m/z(268, M+H).

To a mixture containing crude 5-bromo-3-chloro-6-methylpyridin-2-ol (1.5g, 6.74 mmol) and K₂CO₃ (1.9 g, 13.49 mmol) in DMF (10 mL) was added Met(0.843 mL, 13.49 mmol). The reaction mixture was stirred for 20 h anddiluted with ethyl acetate (100 mL). The resulting solids were filteredthrough a plug of celite. The filtrate was washed with aqueous 10% LiClsolution (2×30 mL) and saturated aqueous NaCl solution (10 mL). Theaqueous washes were combined and extracted with ethyl acetate (50 mL)and the ethyl acetate layer washed again with 10% LiCl aqueous solution(1×20 mL) and saturated aqueous NaCl solution (10 mL). The organicextracts were combined, dried (Na₂SO₄), filtered and concentrated. Thecrude product was dissolved in a small amount of DCM and charged to anISCO silica gel 40 g column which was eluted over a 15 min gradient with5%-100% hexanes/ethyl acetate to afford impure5-bromo-3-chloro-1,6-dimethylpyridin-2(1H)-one (800 mg). LCMS MH⁺: 238.HPLC Ret. Time 0.72 min. Method B1. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.65 (s, 1H), 3.68-3.66 (s, 3H), 2.53 (s, 3H).

Fragment 6: 5-bromo-3-chloro-1-methylpyridin-2(1H)-one

5-bromo-3-chloropyridin-2(1H)-one (400 mg, 1.919 mmol) was stirred withiodomethane (350 μl, 2.303 mmol) and potassium carbonate (530 mg, 3.84mmol) in DMF (6397 μl) in a 20 mL scintillation vial at room temperaturefor 3 h. The reaction mixture was partitioned between 1:1 water andethyl acetate (˜20 mL total volume). The organic phase was extractedwith brine (2×10 mL), then dried over sodium sulfate and filtered.Excess solvent was evaporated from the filtered organic phase to yield5-bromo-3-chloro-1-methylpyridin-2(1H)-one (458.7 mg, 1.856 mmol, 97%yield, 90% purity) as a white solid. LCMS MH⁺: 223.8. HPLC Ret. Time0.64 min. Method B1. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.61 (d, J=2.6 Hz,1H), 7.41 (d, J=2.6 Hz, 1H), 3.61 (s, 3H).

Fragment Structure Name CAS number F-7

6-bromo-2-methylpyridazin- 3(2H)-one 10071-38-2 F-8

5-bromo-1-methylpyrazin- 2(1H)-one 1243288-53-0 F-9

3-amino-5-bromo-1- methylpyridin-2(1H)-one 910543-72-5 F-10

5-bromo-3-fluoro-1- methylpyridin-2(1H)-one 1352152-46-5 F-11

6-chloro-2,5-dimethylpyridazin- 3(2H)-one 1114563-59-5 F-12

6-chloro-2,4-dimethylpyridazin- 3(2H)-one 1114563-58-4 F-13

5-bromo-1,3- dimethylpyrimidine- 2,4(1H,3H)-dione 7033-39-8 F-14

5-bromo-1-isopropylpyridin- 2(1H)-one 851087-08-6 F-15

5-bromo-1-methylpyridin- 2(1H)-one 81971-39-3 F-16

3-amino-5-bromo-1,4- dimethylpyridin-2(1H)-one 1446237-41-7 F-17

5-bromo-1-methyl-3- (trifluoromethyl)pyridin-2(1H)- one 214342-73-1 F-18

5-bromo-1-(2-hydroxy-2- methylpropyl)pyridin-2(1H)- one 1193335-01-1F-19

2-(5-bromo-2-oxopyridin- 1(2H)-yl)acetamide 924712-35-6

Fragment 20: 5-chloro-1,3-dimethylpyrazin-2(1H)-one

A solution containing 3,5-dichloro-1-methylpyrazin-2(1H)-one (300 mg,1.676 mmol) (CAS 87486-33-7), tetramethyltin (0.256 mL, 1.844 mmol) andtetrakis(triphenylphosphine)palladium(0) (48.4 mg, 0.042 mmol) in DMF (2mL) in a Biotage microwave vial was sealed with a Teflon-lined septacap. The vial was evacuated under vacuum and backfilled with nitrogengas, using a needle from a vacuum manifold. The procedure repeated andthe nitrogen line removed. The vial was heated in a Biotage microwave at150° C. for 20 min. The reaction mixture was cooled to room temperatureand diluted with ethyl acetate (50 mL) and washed with aqueous 10% NaFsolution (2×10 mL) and saturated aqueous NaCl solution (1×10 mL), dried(Na₂SO₄), filtered and concentrated. The crude product was dissolved ina small amount of DCM and charged to a 10 g ISCO silica gel column,placed on a Teledyne ISCO system and eluted over a 20 min gradient using0%-100% hexanes/ethyl acetate eluent to afford5-chloro-1,3-dimethylpyrazin-2(1H)-one (170 mg, 1.072 mmol, 64.0%yield). LCMS MH⁺: 159.0. HPLC Ret. Time 0.52 min. Method B1. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.13 (bm, 1H), 3.52 (s, 3H), 2.48 (d, J=0.6 Hz,3H).

Fragment 21: 6-Chloro-2,4,5-trimethylpyridazin-3(2H)-one

3,6-dichloro-4,5-dimethylpyridazine (1 g, 5.65 mmol) was suspended inwater (10 mL) and powdered KOH (1.585 g, 28.2 mmol) was added. Themixture was heated at 120° C. for 2 h in a sealed pressure vessel,cooled to room temperature and acidified to pH 5 with concentratedaqueous HCl. The resulting solids were filtered and washed with water(˜5 mL) and dried to afford pure 6-chloro-4,5-dimethylpyridazin-3-ol(700 mg, 4.41 mmol, 78% yield), m/z (159, M+H).

To a mixture containing 6-chloro-4,5-dimethylpyridazin-3-ol (100 mg,0.631 mmol) and K₂CO₃ (349 mg, 2.52 mmol) in DMF (1 mL) was added MeI(0.079 mL, 1.261 mmol). The mixture was stirred for 2 h, diluted withwater (10 mL) and extracted with ethyl acetate (4×15 mL). The extractswere combined and washed with 10% LiCl (1×10 mL) and saturated aqueousNaCl solution (10 mL), dried, filtered and concentrated. The crudematerial was dissolved in a small amount of DCM and charged to an ISCOsilica gel 12 g column, which was eluted over a 10 min gradient with5%-100% hexanes/ethyl acetate to afford6-chloro-2,4,5-trimethylpyridazin-3(2H)-one (100 mg, 0.579 mmol, 92%yield), m/z (173, M+H). LCMS MH⁺: 173. HPLC Ret. Time 0.68 min. MethodB1. ¹H NMR (400 MHz, CHLOROFORM-d) δ 3.76 (s, 3H), 2.27 (d, J=0.7 Hz,3H), 2.24 (d, J=0.7 Hz, 3H).

Fragment 22: 6-Chloro-2-ethyl-4,5-dimethylpyridazin-3(2H)-one

To a solution containing 6-chloro-4,5-dimethylpyridazin-3-ol (100 mg,0.631 mmol) (see fragment 16) and iodoethane (0.051 mL, 0.631 mmol) inDMF (2.5 mL) was added K₂CO₃ (349 mg, 2.52 mmol). The reaction mixturewas stirred for 20 h, diluted with ethyl acetate (50 mL) and washed withwater (1×20 mL) and aqueous 10% LiCl solution (2×10 mL). The aqueousfractions were washed, combined and back extracted with ethyl acetate(20 mL). The organic extracts were combined and washed with saturatedaqueous NaCl solution, dried (Na₂SO₄), filtered and concentrated. Thecrude product was dissolved in a small amount of DCM and charged to anISCO silica gel 120 g ISCO Column which was eluted over a 15 mingradient with 5%-100% hexanes/ethyl acetate to afford6-chloro-2-ethyl-4,5-dimethylpyridazin-3(2H)-one (105 mg, 0.563 mmol,89% yield). LCMS MH⁺: 187. HPLC Ret. Time 0.77 min. Method B1. ¹H NMR(400 MHz, CHLOROFORM-d) δ 4.18 (q, J=7.1 Hz, 2H), 2.27 (s, 3H), 2.23 (s,3H), 1.42-1.35 (t,7.1 Hz, 3H).

Fragment 23: 6-Chloro-2-ethyl-4-methylpyridazin-3(2H)-one

To a mixture containing 6-chloro-4-methylpyridazin-3(2H)-one (250 mg,1.729 mmol) and K₂CO₃ (598 mg, 4.32 mmol) in DMF (2.5 mL) was addedethyl iodide (0.210 mL, 2.59 mmol). The reaction mixture was stirred atroom temperature for 22 h. The reaction mixture was diluted with water(25 mL) and extracted with ethyl acetate (3×40 mL). The combinedextracts were washed with 10% LiCl (2×20 mL) and saturated aqueous NaClsolution (1×20 mL), dried (Na₂SO₄), filtered and concentrated to affordcrude product. The crude product was dissolved in a small amount of DCMand charged to an ISCO silica gel 12 g ISCO column which was eluted overa 10 min gradient with 0%-100% hexanes/ethyl acetate to afford6-chloro-2-ethyl-4-methylpyridazin-3(2H)-one (250 mg, 1.448 mmol, 84%yield), m/z (173, M+H). LCMS MH⁺: 173. HPLC Ret. Time 0.70 min. MethodB1. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.06 (q, J=1.2 Hz, 1H), 4.17 (q,J=7.2 Hz, 2H), 2.21 (d, J=1.2 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H).

Fragment 24: 5-Bromo-3-methoxy-1,6-dimethylpyridin-2(1H)-one

A solution containing 5-bromo-3-methoxy-6-methylpyridin-2-amine (1 g,4.61 mmol) in sulfuric acid (2 mL, 37.5 mmol) and 4 mL water was cooledin an ice bath. A solution of sodium nitrite (0.636 g, 9.21 mmol) inwater (1 mL) was added dropwise and the ice bath was removed. Thereaction mixture was stirred at room temperature for 1 h. Water (25 mL)was added and the mixture was cooled in an ice bath and stirred for 20min. The resulting solids were filtered, washed with water and dried toafford 5-bromo-3-methoxy-6-methylpyridin-2-ol (700 mg, 3.21 mmol, 69.7%yield), m/z (220, M+H).

To a solution containing 5-bromo-3-methoxy-6-methylpyridin-2-ol (700 mg,3.21 mmol) in DMF (7.5 mL) was added K₂CO₃ (887 mg, 6.42 mmol) followedby the addition of MeI (0.401 mL, 6.42 mmol). The mixture was stirredfor 2 h, diluted with ethyl acetate (100 mL) and the solids filteredthrough a pad of celite. The filtrate was washed with aqueous 10% LiClsolution (3×25 mL), saturated aqueous NaCl solution (25 m), dried(Na₂SO₄), filtered and concentrated. The crude product was dissolved ina small amount of DCM and charged to a 24 g ISCO silica gel column,which was eluted over a 15 min gradient with 5%-100% DCM/EtOAc to afford5-bromo-3-methoxy-1,6-dimethylpyridin-2(1H)-one (525 mg, 2.262 mmol,70.5% yield). LCMS MH+: 233.9. HPLC Ret. Time 0.65 min. Method B1. ¹HNMR (400 MHz, CHLOROFORM-d) δ 6.74 (s, 1H), 3.82 (s, 3H), 3.64 (s, 3H),2.48 (s, 3H).

Fragment 25: 5-Bromo-3-methoxy-1,4-dimethylpyridin-2(1H)-one

To a mixture of 5-bromo-3-methoxy-4-methylpyridin-2-amine (0.45 g, 2.073mmol) in concentrated H₂SO₄ (1 mL) and water (3 mL) was added a solutionof sodium nitrite (0.215 g, 3.11 mmol) in water (1 mL) at 0° C. Themixture was allowed to come to room temperature and stirred for 1 h. Icecold water (10 mL) was added and the precipitate was filtered and washedwith ice water and dried to afford5-bromo-3-methoxy-4-methylpyridin-2-ol (250 mg, 1.147 mmol, 55.3%yield).

To a mixture containing 5-bromo-3-methoxy-4-methylpyridin-2-ol (250 mg,1.147 mmol) and K₂CO₃ (396 mg, 2.87 mmol) in DMF (2.5 mL) was added MeI(0.143 mL, 2.293 mmol). The reaction mixture was stirred for 20 h anddiluted with ethyl acetate (50 mL). The solids were filtered through apad of celite and the filtrate washed with aqueous 10% LiCl solution(3×10 mL) and saturated aqueous NaCl solution (10 mL), dried (Na₂SO₄),filtered and concentrated to afford crude product. The crude product wasdissolved in a small amount of DCM and charged to a 12 g ISCO silica gelcolumn, which was eluted over a 10 min gradient with 5%-100%hexanes/ethyl acetate to afford5-bromo-3-methoxy-1,4-dimethylpyridin-2(1H)-one (218 mg, 0.939 mmol, 82%yield). LCMS MH⁺: 233.9. HPLC Ret. Time 0.67 min. Method B1. ¹H NMR (400MHz, DMSO-d₆) δ 7.88 (s, 1H), 3.75 (s, 2H), 3.43 (s, 3H), 2.15 (s, 3H).

Fragment 26:5-Chloro-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one

3-bromo-5-chloropyridin-2(1H)-one (Combi-Blocks, CAS: 137628-16-1, 170mg, 0.816 mmol) was stirred with iodomethane (149 μl, 0.979 mmol) andpotassium carbonate (564 mg, 4.08 mmol) in DMF (2719 μl) in a 20 mL vialfor 2 h at room temperature. The reaction mixture was partitionedbetween water and ethyl acetate (4 mL total volume). The aqueous phasewas extracted with ethyl acetate (2×1.5 mL). The combined organic phaseswere extracted with brine (2×10 mL). Excess solvent was evaporated fromthe combined organic phases to afford3-bromo-5-chloro-1-methylpyridin-2(1H)-one (151.8 mg, 0.662 mmol, 81%yield) as a pale yellow solid. M+H⁺=221.9, 223.9. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.75 (d, J=2.7 Hz, 1H), 7.38 (d, J=2.7 Hz, 1H), 3.62 (s,3H).

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(31.1 mg, 0.149 mmol) and 3-bromo-5-chloro-1-methylpyridin-2(1H)-one (35mg, 0.157 mmol) were weighed into a 1-dram vial. THF (1049 μl) was addedto the vial, followed by 2 M aqueous tripotassium phosphate (236 μl,0.472 mmol). The reaction mixture was degassed by bubbling nitrogenthrough the solution for 2 min. 2nd generation XPhos precatalyst (4.95mg, 6.29 μmol) were added to the reaction mixture. The reaction mixturewas placed under a nitrogen atmosphere and stirred at 60° C. for 3 h.The reaction mixture was cooled to room temperature and the aqueousphase was removed, and excess solvent was evaporated from the organicphase. The residue was taken up in DCM (3 mL) and purified by flashchromatography on a 4 g silica column, eluting with dichloromethane andmethanol on an ISCO Rf instrument to afford5-chloro-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (30.8mg, 0.131 mmol, 83% yield) as a pale yellow solid. LCMS MH⁺: 224.0. HPLCRet. Time 0.63 min. Method B1. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.36 (s,1H), 7.89-7.83 (m, 1H), 7.57 (d, J=2.7 Hz, 1H), 7.26 (d, J=2.8 Hz, 1H),3.94 (s, 3H), 3.60 (s, 3H).

Fragment 27:5-Chloro-1,4-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one

3-bromo-5-chloro-4-methylpyridin-2-ol (Combi-Blocks, CAS: 1199773-45-9,170 mg, 0.764 mmol) was stirred with iodomethane (140 82 l, 0.917 mmol)and potassium carbonate (528 mg, 3.82 mmol) in DMF (2547 μl) in a 20 mLvial at room temperature for 40 min. The reaction mixture waspartitioned between water and ethyl acetate (4 mL total volume), and theaqueous phase was extracted with ethyl acetate (2×1.5 mL). The combinedorganic phases were extracted with brine (2×10 mL). Excess solvent wasevaporated from the combined organic phases to afford3-bromo-5-chloro-1,4-dimethylpyridin-2(1H)-one (217.2 mg, 0.735 mmol,96% yield) as a pale yellow solid. m/z (237.9, 239.9, M+H). ¹H NMR: (400MHz, METHANOL-d₄) δ 7.89 (s, 1H), 3.61 (s, 3H), 2.50 (s, 3H).

1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(31.7 mg, 0.152 mmol) and 3-bromo-5-chloro-1,4-dimethylpyridin-2(1H)-one(30 mg, 0.127 mmol) were weighed into a 1-dram vial. THF (846 μl) wasadded to the vial, followed by 2 M aqueous tripotassium phosphate (19082 l, 0.381 mmol). The reaction mixture was degassed by bubblingnitrogen through the solution for 2 min. 2nd Generation XPhosprecatalyst (3.99 mg, 5.07 μmol) was added to the reaction mixture. Thereaction mixture was placed under a nitrogen atmosphere and stirred at60° C. for 20 h. The aqueous phase was removed, and excess solvent wasevaporated from the organic phase. The residue was taken up in DCM (3mL) and purified by flash chromatography on a 4 g silica column, elutingwith ethyl acetate and hexanes on an Isco Rf instrument. The product didnot elute, so the column was then eluted with 1-15% MeOH indichloromethane. Excess solvent was evaporated from theproduct-containing fractions to afford5-chloro-1,4-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one(12.8 mg, 0.053 mmol, 41.6% yield) as a white solid. LCMS MH⁺: 238.0.HPLC Ret. Time 0.64 min. Method B1. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.85 (s, 1H), 7.62 (s, 1H), 7.33 (s, 1H), 3.96 (s, 3H), 3.56 (s, 3H),2.39 (s, 3H).

Fragment 28: 5-Bromo-3-chloro-1-ethylpyridin-2(1H)-one

5-bromo-3-chloropyridin-2(1H)-one (150 mg, 0.720 mmol) was stirred withiodoethane (69.4 82 l, 0.864 mmol) and potassium carbonate (497 mg, 3.60mmol) in DMF (2399 μl) in a 20 mL vial containing a Teflon-coated stirbar at room temperature for 19 h. The reaction mixture was partitionedbetween water and ethyl acetate (8 mL total volume). The aqueous phasewas extracted with ethyl acetate (2×2 mL). The combined organic phaseswere then dried (Na₂SO₄), filtered and concentrated to afford5-bromo-3-chloro-1-ethylpyridin-2(1H)-one (113.3 mg, 0.383 mmol, 53.3%yield) as a white solid. LCMS MH⁺: 237.9. HPLC Ret. Time 0.72 min.Method B1.

Fragment 29: 5-Bromo-3-chloro-1,4-dimethylpyridin-2(1H)-one

5-bromo-4-methylpyridin-2-ol (1.00 g, 5.32 mmol) and N-chlorosuccinimide(0.473 mL, 5.85 mmol) were suspended in DCM (21.27 mL) in a 40 mLscintillation vial. The reaction mixture was stirred at room temperaturefor 3 h, then at 40° C. for 17 h. The reaction mixture was heated to 50°C. for 30 min, then allowed to cool to room temperature. The reactionmixture was washed with water (2×10 mL) and then brine (1×5 mL). Theyellow solid began to crash out of the organic solution after the secondaqueous wash. Excess solvent was evaporated from the organic phase. Theresulting residue was taken up in DMF (15 mL) in a 40 mL scintillationvial. Potassium carbonate (1.470 g, 10.64 mmol) and iodomethane (1.200mL, 7.89 mmol) were added to the vial, and the resulting reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas partitioned between water and ethyl acetate, total volume˜30 mL. Thephases were separated, and the aqueous phase was extracted with ethylacetate (2×10 mL). The combined organic phases were dried over sodiumsulfate, filtered, and excess solvent was evaporated off. The residuewas taken up in DCM/MeOH and dried onto silica, then purified by flashchromatography on a 24 g silica column, eluting with ethyl acetate andhexanes on an ISCO Rf instrument. The product-containing fractions werepooled and solvent was evaporated off to yield5-bromo-3-chloro-1,4-dimethylpyridin-2(1H)-one (1.0025 g, 4.03 mmol, 76%yield) as a yellow-orange solid. LCMS MH⁺: 237.8. HPLC Ret. Time 0.70min. Method B1. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.46 (s, 1H), 3.60 (s,3H), 2.46 (s, 3H).

Fragment 30:5-Bromo-1-(2-hydroxy-2-methylpropyl)-3-methylpyridin-2(1H)-one

To a 20 mL vial fitted with a Teflon lined septum were added5-bromo-3-methylpyridin-2(1H)-one (100 mg, 0.532 mmol), DMF (1064 4),potassium carbonate (73.5 mg, 0.532 mmol), and 2,2-dimethyloxirane (38.3mg, 0.532 mmol). The vial was sealed. The reaction mixture was stirredat 65° C. for 3 h. The reaction mixture was cooled to room temperatureand stirred for 20 h. The mixture was diluted with water (10 mL) andextracted with ethyl acetate (3×5 mL). Organic layers are combined,concentrated and purified by ISCO (12 g silica, 100% hexanes-100% ethylacetate). Like fractions were combined and concentrated under vacuum toafford 5-bromo-1-(2-hydroxy-2-methylpropyl)-3-methylpyridin-2(1H)-one(101 mg, 0.369 mmol, 69.4% yield). LC MS at t=peak #1, 0.67 min.(m⁺¹=260) showed one major product that was consistent with Fragment 30.LCMS MH⁺: 260. HPLC Ret. Time 0.67 min. Method B1.

Fragment 31A:

To a mixture of 5-bromo-1,3-dimethylpyridin-2(1H)-one (300 mg, 1.485mmol) (F1) and NBS (264 mg, 1.485 mmol) in CCl₄ (20 mL) was added AIBN(24.38 mg, 0.148 mmol). The reaction mixture was heated at 90° C. for 1hour and then cooled to room temperature. The reaction mixture wasdiluted with dichloromethane and washed with saturated NaHCO₃. Theorganic layer was dried with MgSO₄, filtered and concentrated to afford5-bromo-3-(bromomethyl)-1-methylpyridin-2(1H)-one (420 mg, 1.4 mmol,100% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.58 (d, J=2.6 Hz, 1H),7.46 (d, J=2.6 Hz, 1H), 4.43 (s, 2H), 3.59 (s, 3H).

To a mixture of MeOH (0.079 mL, 1.950 mmol) in THF (5 mL) was addedsodium hydride (90 mg, 2.250 mmol). After stirring 30 minutes,5-bromo-3-(bromomethyl)-1-methylpyridin-2(1H)-one (421 mg, 1.5 mmol) wasadded. The reaction mixture was stirred at room temperature for 3 hours.The reaction was quenched with water. The reaction mixture was dilutedwith ethyl acetate and washed with saturated NaCl. The organic layer wasdried with MgSO₄, filtered and concentrated. The crude material waspurified on a silica gel cartridge (24 g) using an ethyl acetate/hexanegradient (0-100% ethyl acetate over 12.5 min) to afford5-bromo-3-(methoxymethyl)-1-methylpyridin-2(1H)-one (160 mg, 0.689 mmol,46.0% yield). LCMS MH⁺: 217.9. HPLC Ret. Time 0.64 min. Method Acquity.¹H NMR (400 MHz, CHLOROFORM-d) δ 7.50 (dt, J=2.8, 1.3 Hz, 1H), 7.38 (d,J=2.6 Hz, 1H), 4.44-4.36 (m, 2H), 3.55 (s, 3H), 3.49 (s, 3H).

The following fragments were prepared according to the generalprocedures for the above fragments, using the indicated startingmaterials and synthetic methods. The HPLC method was Method B1.

TABLE 1 Ret Frag. Starting Synthetic Mol. LCMS Time No. Structurematerial Method Weight MH⁺ (min) F31B

5-bromo-6- methylpyridin- 2(1H)-one 1 202.0 203.9 0.62 F32

5-bromo-4- methylpyridin- 2(1H)-one 1 202.0 203.9 0.61 F33

5-bromo-3,4- dimethylpyridin-2-ol 1 229.0 230.0 0.76 F34

5-bromo-3- methoxypyridine- 2-ol 1 218.0 219.9 0.57 F35

5-bromo-4-methyl-2- oxo-1,2- dihydropyridine-3- carbonitrile 1 227.0228.7 0.63 F36

5-bromo-2-hydroxy- 6- methylnicotinonitrile 1 227.0 228.9 0.62 F37

5-bromo-3- methylpyridin- 2(1H)-one 1 216.0 217.9 0.73 F38

5-bromo-3-ethyl-6- methylpyridin-2-ol 1 244.1 246.0 0.87 F39

ethyl 5-bromo-2- oxo-1,2- dihydropyridine-3- carboxylate 1 245.0 245.90.59 F40

5-bromo-3- methylpyridin- 2(1H)-one 2 246.1 248 0.70 F41

5-bromo-3- methylpyridin- 2(1H)-one 2 278.1 280 0.87 F42

5-bromo-3- methylpyridin- 2(1H)-one 2 242.1 244 0.80 F43

5-bromo-3- methylpyridin- 2(1H)-one 2 232.1 234 0.57 F44

5-bromo-3- methylpyridin- 2(1H)-one 2 252.1 254 0.74 F45

5-bromo-3- methylpyridm- 2(1H)-one 2 270.0 271.9 0.80 F46

5-bromo-3- methylpyridin- 2(1H)-one 2 258.1 260 0.96 F47

5-bromo-3- methylpyridin- 2(1H)-one 2 246.1 248 0.61 F48

5-bromo-3- cyanopyridin-2(1H)- one 1 211.9 212.7 0.55 F49

5-bromo-3-ethyl-6- methylpyridin-2-ol 1 229.01 230.0 0.80

EXAMPLE 15-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one

To a mixture containing 5-bromo-1-methylpyridin-2(1H)-one (15.05 mg,0.080 mmol), tert-butyl4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate(25 mg, 0.053 mmol), and Xphos Pd G2 (2.100 mg, 2.67 μmol) in a screwcap vial was added THF (1 mL) followed by an aqueous solution oftripotassium phosphate (100 μL, 0.300 mmol). The vial was fitted with aTeflon lined septum cap. The vial was evacuated under vacuum (via aneedle from a nitrogen/vacuum manifold line) and backfilled withnitrogen gas. The evacuation procedure was repeated three times. Theneedle was removed and the vial was heated at 65° C. for 18 h. Thereaction mixture was concentrated to dryness and treated with TFA (1 mL)for 30 min to facilitate the removal of the tert-butyloxycarbonyl group.The reaction mixture was re-concentrated to dryness and re-dissolved inDMF (2 mL). The sample was filtered through an Acrodisc, 13 mm, 0.45micron nylon membrane syringe filter and was purified via preparativeLC/MS with using condition Method D2 to afford5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(12 mg, 0.034 mmol, 64.3% yield). LCMS MH⁺: 350. HPLC Ret. Time 0.58min. Method B1. ¹H NMR (500 MHz, DMSO-d₆) δ 10.84 (s, 1H), 7.81 (d,J=2.1 Hz, 1H), 7.53 (dd, J=9.3, 2.3 Hz, 1H), 7.47 (s, 1H), 7.23 (d,J=8.2 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.52 (d, J=9.3 Hz, 1H), 3.52 (s,3H), 3.19-3.09 (m, 2H), 2.77-2.66 (m, 2H), 1.84 (m, 3H), 1.80-1.75 (m,2H), 1.72-1.59 (m, 2H), 1.39 (d, J=7.0 Hz, 6H).

EXAMPLE 25-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one

Intermediate 2A: tert-butyl4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate

To a mixture containing tert-butyl4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate(2434 mg, 5.20 mmol), 5-bromo-1,3-dimethylpyridin-2(1H)-one (1000 mg,4.95 mmol), and Xphos Pd G2 (97 mg, 0.124 mmol) in a screw cap vial wasadded THF (25 mL) followed by an aqueous solution of potassiumphosphate, tribasic (4.95 mL, 14.85 mmol). The vial was fitted with aTeflon lined septum cap. The vial was evacuated under vacuum (via aneedle from a nitrogen/vacuum manifold line) and backfilled withnitrogen gas. The evacuation procedure was repeated three times. Theneedle was removed and the vial was heated at 65° C. for 2 h. Thereaction mixture was cooled to room temperature, diluted with ethylacetate (50 mL) and washed with saturated aqueous NaCl solution (10 mL),dried (Na₂SO₄), filtered and concentrated to afford crude material. Thecrude product was dissolved in a small amount of DCM and charged to a 40g ISCO silica gel column, which was eluted over a 15 min gradient with5%-100% hexanes/ethyl acetate to afford tert-butyl4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate, 2.1 g (90% yield) m/e (464, M⁺¹).

EXAMPLE 2

The purified tert-butyl4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylatewas dissolved in DCM (10 mL) and treated with TFA (10 mL). The reactionmixture was stirred for 30 min and concentrated to dryness. The residuewas treated with saturated aqueous ammonium hydroxide (20 mL) andstirred for 30 min. The resulting fine suspension was filtered andrinsed with additional ammonium hydroxide and dried to afford5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(1.55 g, 4.26 mmol, 86% yield) as a yellow solid. LCMS MH⁺: 364. HPLCRet. Time 0.63 min. Method B1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (s,1H), 7.66 (d, J=2.3 Hz, 1H), 7.48 (s, 1H), 7.44 (dd, J=2.3, 1.1 Hz, 1H),7.23 (d, J=8.3 Hz, 1H), 6.94 (dd, J=8.4, 1.5 Hz, 1H), 3.91 (s, 1H), 3.54(s, 3H), 3.21-3.10 (m, 3H), 2.77-2.65 (m, 3H), 1.84 (s, 3H), 1.82-1.62(m, 4H), 1.41 (s, 3H), 1.39 (s, 3H).

EXAMPLE 35-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one

Intermediate 3A: tert-butyl4-(2-(5-chloro-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate

To a mixture containingtert-butyl4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate(1.0 g, 2.135 mmol), 5-bromo-3-chloro-1,6-dimethylpyridin-2(1H)-one(0.606 g, 2.56 mmol), and Pd(dppf)Cl₂ (0.078 g, 0.107 mmol) in a screwcap vial was added THF (10 mL) followed by the addition of 3 M aqueoussolution of potassium phosphate, tribasic (2.135 mL, 6.40 mmol). Thevial was fitted with a Teflon lined septum cap. The vial was evacuatedunder vacuum (via a needle from a nitrogen/vacuum manifold line) andbackfilled with nitrogen gas. The procedure was repeated three times.The needle was removed and the vial was heated at 65° C. for 20 h. Thereaction mixture was cooled to room temperature, diluted with ethylacetate (10 mL) and washed with saturated aqueous NaCl solution (5 mL),dried (Na₂SO₄), filtered and concentrated to afford crude material. Thecrude product was dissolved in a small amount of DCM and charged to a 80g ISCO column which was eluted over a 20 min gradient with 5%-100%hexanes/ethyl acetate to afford tert-butyl4-(2-(5-chloro-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate, m/z (448.2, M+H), which was contaminated withdimer, m/z (804, M+H), 700 mg.

EXAMPLE 3

To a mixture containing crude tert-butyl4-(2-(5-chloro-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate(25 mg, 0.050 mmol), bis(triphenylphosphine)palladium(II) dichloride(1.762 mg, 2.510 μmol), and lithium chloride (4.26 mg, 0.100 mmol) in ascrew cap vial was added DMF (0.5 mL) followed by the addition oftetramethyltin (0.014 mL, 0.100 mmol). The vial was fitted with a Teflonlined septum cap and the system was evacuated under vacuum (via a needlefrom a nitrogen/vacuum manifold line) and backfilled with nitrogen gas.The procedure was repeated three times. The needle was removed and thevial was heated at 100° C. for 6 h. Additional Pd catalyst (˜1 mg) andtetramethyl tin (20 μL) were added and the reaction mixture was heatedfor an additional 18 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate (5 mL) and washed with 10%aqueous LiCl solution (3×2 mL), dried (Na₂SO₄), filtered andconcentrated.

The crude tert-butyl4-(3-isopropyl-2-(1,2,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidine-1-carboxylatewas suspended in DCM/TFA (1/1) (1 mL) for 30 min to facilitate theremoval of the tert-butyloxycarbonyl group. The reaction mixture wasconcentrated and the crude material was purified via preparativeHPLC/MS. Fractions containing the product were combined and dried viacentrifugal evaporation to afford TFA salt. The material was free basedby suspending the salt in concentrated ammonium hydroxide (1 mL) andstirring for 20 min. The solids were filtered and dried to afford5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(5 mg, 0.013 mmol, 25% yield). LCMS MH⁺: 378. HPLC Ret. Time 0.63 min.Method B1. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.56-7.52 (m, 1H), 7.34 (s,1H), 7.26 (d, J=8.3 Hz, 1H), 7.03 (dd, J=8.4, 1.3 Hz, 1H), 3.69 (s, 3H),3.23-3.15 (m, 2H), 3.01-2.90 (m, 1H), 2.85-2.70 (m, 3H), 2.31 (s, 3H),2.16 (s, 3H), 1.95-1.87 (m, 2H), 1.85-1.71 (m, 2H), 1.44-1.33 (m, 6H).

The following examples were prepared according to the general proceduresfor Examples 1 and 2 using the indicated fragment.

TABLE 2 Ret Ex. LCMS Time HPLC No. Structure Fragment MH⁺ (min) Method 4

F-8 351.1 1 QC-ACN- TFA- XB 5

F-7 351.2 1.2 QC-ACN- AA-XB 6

F-31B 364.1 0.60 Method B1 8

F-32 364.2 0.99 QC-ACN- AA-XB 9

F-9 365.2 1.07 QC-ACN- AA-XB 10

F-11 364.9 1.01 QC-ACN- AA-XB 11

F-12 365.3 0.65 Method B1 12

F-20 365.3 0.62 Method B1 13

F-10 368.2 0.96 QC-ACN- AA-XB 14

F-4 378.3 0.65 Method B1 15

F-37 378.2 1.16 QC-ACN- AA-XB 16

F-14 378.1 1.12 QC-ACN- TFA-XB1 17

F-21 379.3 1.05 QC-ACN- AA-XB 18

F-23 379 1.36 QC-ACN- AA-XB 19

F-16 379.3 0.91 QC-ACN- AA-XB 20

F-34 380.3 0.59 Method B1 21

F-13 381.3 1.27 QC-ACN- AA-XB 22

F-6 384.3 1.14 QC-ACN- TFA-XB 23

F-36 389.2 0.64 Method B1 24

F-35 389.2 0.64 Method B1 25

F-49 392.1 0.71 Method B1 26

F-33 392.4 0.68 Method B1 27

F-22 393.2 1.23 Method B1 28

F-24 394.2 0.61 Method B1 29

F-25 394.1 0.63 Method B1 30

F-43 394.2 1.05 QC-ACN- AA-XB 31

F-29 398.2 1.19 QC-ACN- TFA-XB 32

F-28 398.2 1.39 QC-ACN- TFA-XB 33

F-5 398.1 0.66 Method B1 34

F-42 404 1.33 QC- ACN- AA- XB 35

F-38 406.3 0.73 Method B1 36

F-2 406 1.34 QC- ACN- TFA- XB 37

F-39 408 1.19 QC- ACN- TFA- XB 38

F-47 408.2 1.05 QC- ACN- AA- XB 39

F-40 408.1 1.27 QC-ACN- TFA-XB 40

F-44 414.3 1.28 QC-ACN- AA-XB 41

F-17 417.3 0.71 Method B1 42

F-46 420.3 1.36 QC-ACN- AA-XB 43

F-30 422 1.39 QC-ACN- AA-XB 44

F-3 426.2 1.46 QC-ACN- TFA-XB 45

F-45 432.2 1.54 QC-ACN- AA-XB 46

F-41 440 1.46 QC-ACN- AA-XB 47

F-48 375.3 0.63 Method B1 48

F-18 408.3 1.29 QC-ACN- AA-XB 49

F-19 392.9 0.74 QC-ACN- AA-XB

EXAMPLE 505-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one

tert-Butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indole-1-carboxylate(30 mg, 0.051 mmol) and3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (21.06 mg, 0.103mmol) were weighed into a 1-dram vial. THF (0.514 mL) was added to thevial, followed by aqueous tripotassium phosphate (2 M, 0.103 mL, 0.205mmol). The reaction mixture was degassed by bubbling nitrogen throughthe solution for 2 min. Second generation XPhos precatalyst (1.212 mg,1.541 μmol) was added and the reaction mixture was placed under anitrogen atmosphere and stirred at 65° C. for 3 h. The reaction mixturewas cooled to room temperature. The reaction mixture was partitionedbetween water and ethyl acetate (˜2 mL each), separated, and the aqueousphase was extracted with ethyl acetate (2×2 mL). Excess solvent wasevaporated from the organic phase. The resulting residue wasBoc-deprotected with 2:1 trifluoroacetic acid/dichloromethane (1.2 mL,0.051 mmol), stirring for 45 min at room temperature. Toluene (˜0.1 mL)was added, and excess solvent was evaporated from the reaction. Thecrude material was purified via preparative LC/MS. Fractions containingthe product were combined and dried via centrifugal evaporation toafford5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(9.4 mg, 0.021 mmol, 40% yield, 94% purity). LCMS MH⁺: 427.3. HPLC Ret.Time 1.01 min. Method QC-ACN-TFA-XB. ¹H NMR (500 MHz, DMSO-d₆) δ 11.00(s, 1H), 9.08 (br. s., 1H), 8.42 (d, J=8.2 Hz, 2H), 7.94 (s, 1H), 7.90(d, J=2.4 Hz, 1H), 7.66 (dd, J=7.8, 5.0 Hz, 1H), 7.53 (s, 1H), 7.31 (d,J=8.2 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 3.59-3.49 (m, 3H), 3.40 (d,J=11.9 Hz, 2H), 3.24 (dt, J=14.0, 6.9 Hz, 1H), 3.09-2.98 (m, 2H),2.96-2.89 (m, 1H), 2.01-1.93 (m, 2H), 1.93-1.81 (m, 2H), 1.43 (d, J=7.0Hz, 6H).

The following examples were prepared according to the general procedurefor Example 50 using the indicated starting material.

TABLE 3 Starting Ret Ex. coupling LCMS Time HPLC No. Structure partnerMH⁺ (min) Method 51

4,4,5.5- tetramethyl-2- (prop-1-en-2-yl)- 1,3,2- dioxaborolane 390.31.31 QC-ACN-TFA-XB 52

(E)-2-(2- cyclopropylvinyl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane416.3 1.47 QC-ACN-TFA-XB 53

phenylboronic acid 426.0 1.45 QC-ACN-TFA-XB 54

pyrimidin-5-yl boronic acid 428.0 1.38 QC-ACN-TFA-XB 55

p-tolylboronic acid 440.3 1.51 QC-ACN-TFA-XB 56

(3-cyanophenyl) boronic acid 451.2 1.34 QC-ACN-TFA-XB 57

(2-methoxypyridin-3- yl)boronic acid 456.9 1.28 QC-ACN-TFA-XB 58

(3-carbamoylphenyl) boronic acid 469.4 1.06 QC-ACN-TFA-XB 59

(3-(methylcarbamoyl) phenyl)boronic acid 482.9 1.21 QC-ACN-TFA-XB 60

(3-acetamidophenyl) boronic acid 483.0 1.29 QC-ACN-TFA-XB 61

(E)-(3,3- dimethylbut-1-en-1-yl) boronic acid 434.1 1.75 QC-ACN-TFA-XB62

(E)-2-(2- cyclopropylvinyl)- 4,4,5,5- tetramethyl-1,3,2- dioxaborolane418 1.3 QC-ACN-TFA-XB 63

Prepared as in example 70 421 1.12 QC-ACN-AA-XB 64

Prepared as in example 70 435.2 1.4 QC-ACN-AA-XB

EXAMPLE 655-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-[3,3′-bipyridin]-2(1H)-one

Intermediate 65A: tert-butyl4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate

5-bromo-3-chloro-1,4-dimethylpyridin-2(1H)-one (0.100 g, 0.423 mmol) wascoupled to tert-butyl4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate(0.172 g, 0.368 mmol) as described above for Intermediate 2A to affordtert-butyl4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate(149.3 mg, 0.285 mmol, 77% yield) as a pale yellow solid. LCMS MH⁺:498.2. HPLC Ret. Time 1.12 min QC-ACN-TFA-XB. ¹H NMR (400 MHz,CHLOROFORM-d) δ 9.03 (s, 1H), 7.60 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.18(s, 1H), 7.12 (dd, J=8.4, 1.5 Hz, 1H), 4.38-4.22 (m, 2H), 3.60 (s, 3H),2.96 (quin, J=7.1 Hz, 1H), 2.87 (t, J=12.2 Hz, 2H), 2.79 (tt, J=12.1,3.2 Hz, 1H), 2.17 (s, 3H), 1.93 (d, J=12.5 Hz, 2H), 1.75 (qd, J=12.6,4.0 Hz, 2H), 1.52 (s, 9H), 1.39 (d, J=7.0 Hz, 6H).

EXAMPLE 65

tert-Butyl 4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (134.3 mg, 0.270mmol) was coupled to pyridin-3-ylboronic acid (66.3 mg, 0.539 mmol).Next, tert-butyl4-(2-(1,4-dimethyl-2-oxo-1,2-dihydro-[3,3′-bipyridin]-5-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate(16.2 mg, 0.030 mmol) was deprotected as described above for Example 50to afford5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-[3,3′-bipyridin]-2(1H)-one(12.0 mg, 0.026 mmol, 85% yield for the deprotection, 94% purity). LCMSMH⁺: 441.3. HPLC Ret. Time 0.78 min. QC-ACN-TFA-XB. ¹H NMR (500 MHz,DMSO-d₆) δ 10.81 (s, 1H), 8.53 (br. s., 1H), 8.44 (br. s., 1H), 7.74 (s,1H), 7.70 (d, J=7.7 Hz, 1H), 7.48 (br. s., 1H), 7.47 (d, J=7.7 Hz, 1H),7.24 (d, J=8.3 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 3.52 (br. s., 3H), 3.17(s, 2H), 3.03-2.94 (m, 1H), 2.72 (br. s., 3H), 1.79 (s, 6H), 1.71 (br.s., 2H), 1.34 (br. s., 6H).

EXAMPLE 663-isopropyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one

Intermediate 66A:tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indole-1-carboxylate

5-Bromo-3-chloro-1-methylpyridin-2(1H)-one (0.390 g, 1.754 mmol) andtert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(0.950 g, 1.671 mmol) were weighed into a 40 mL scintillation vialcontaining a Teflon-coated stir bar and equipped a pressure-release cap.THF (8.35 mL) was added to the vial, followed by tripotassium phosphate(2.506 mL, 5.01 mmol). The reaction mixture was degassed by bubbling N₂through the solution for 5 min. 2nd generation XPhos precatalyst (0.039g, 0.050 mmol) was added to the reaction mixture. The reaction mixturewas placed under an N₂ atmosphere and stirred at 65° C. for 20 h. Thereaction mixture was cooled to room temperature, diluted with ethylacetate (20 mL) and the organic layer was isolated, dried (Na₂SO₄),filtered and concentrated. The residue was taken up in DCM (˜5 mL) andpurified by flash chromatography on a 24 g silica column, eluting with20-100% gradient using ethyl acetate and hexanes to afford tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indole-1-carboxylate(915.5 mg, 1.254 mmol, 75% yield) as a yellow-orange solid. ¹H NMRindicted impurities. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (d, J=8.7 Hz,1H), 7.54 (d, J=1.3 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.22 (dd, J=8.7,1.7 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 4.29 (br. s., 2H), 3.69 (s, 3H),2.99 (spt, J=7.1 Hz, 1H), 2.87 (t, J=12.0 Hz, 2H), 2.78 (tt, J=12.0, 3.4Hz, 1H), 1.90 (d, J=12.3 Hz, 2H), 1.72 (qd, J=12.7, 3.8 Hz, 2H), 1.52(s, 9H), 1.38 (d, J=7.1 Hz, 6H), 1.26 (s, 9H).

Intermediate 66B: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(1-methyl-6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridin-3-yl)-1H-indole-1-carboxylate

Tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indole-1-carboxylate(50 mg, 0.086 mmol) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (31.6 mg,0.188 mmol) were weighed into a 1-dram vial containing a Teflon-coatedstir bar and equipped a pressure-release cap. THF (856 μl) was added tothe vial, followed by aqueous 2 M tripotassium phosphate (128 μl, 0.257mmol). The reaction mixture was degassed by vacuum-purge with nitrogen(3×). Second generation XPhos precatalyst (2.020 mg, 2.57 μmol) wasadded to the reaction mixture. The reaction mixture was placed under anitrogen atmosphere and stirred at 65° C. for 17 h. The reaction mixturewas cooled to room temperature. The aqueous phase was removed, andexcess solvent was evaporated from the organic phase. The resultingresidue was taken up in DCM (3 mL) and purified by flash chromatographyon a 4 g silica column, eluting with ethyl acetate and hexanes to affordtert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(1-methyl-6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridin-3-yl)-1H-indole-1-carboxylate(38.0 mg, 0.058 mmol, 67.7% yield) as a clear, pale yellow glass. m/z(590.1, M+H). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.19 (d, J=8.7 Hz, 1H),7.56-7.53 (m, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.23-7.19 (m, 2H), 5.87 (d,J=1.7 Hz, 1H), 5.30-5.27 (m, 1H), 4.30 (d, J=8.7 Hz, 2H), 3.64 (s, 3H),3.02 (spt, J=7.1 Hz, 1H), 2.86 (t, J=12.3 Hz, 2H), 2.78 (tt, J=12.1, 3.4Hz, 1H), 2.15-2.12 (m, 3H), 1.90 (d, J=12.2 Hz, 2H), 1.72 (qd, J=12.7,3.5 Hz, 2H), 1.52 (s, 9H), 1.41 (s, 9H), 1.38 (d, J=7.1 Hz, 6H).

EXAMPLE 66

Tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(1-methyl-6-oxo-5-(prop-1-en-2-yl)-1,6-dihydropyridin-3-yl)-1H-indole-1-carboxylate(19 mg, 0.032 mmol) was dissolved in MeOH (0.322 mL) and transferredinto the vial containing the 5% Pd on carbon (20 mg, 0.032 mmol) under anitrogen atmosphere. The suspension was stirred and kept under anitrogen atmosphere while triethylsilane (0.051 mL, 0.322 mmol) wasadded dropwise via syringe over ˜5 min. The reaction mixture was stirredat room temperature for 30 min. The reaction mixture was filteredthrough celite, flushing with MeOH. Excess solvent was evaporated fromthe reaction mixture to yield a pale yellow oil.

The intermediate oil was Boc-deprotected with 2:1 trifluoroaceticacid/dichloromethane (1.2 mL, 0.032 mmol) for 40 min. Toluene (˜0.2 mL)was added, and excess solvent was evaporated from the reaction mixture.The resulting residue was taken up in DMF (1.5 mL) and purified viapreparative LC/MS with the following conditions: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing theproduct were combined and dried via centrifugal evaporation to afford3-isopropyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(4.5 mg, 10.9 μmol, 34% yield, 95% purity). LCMS MH⁺: 392.3. HPLC Ret.Time 1.29 min. Method QC-ACN-TFA-XB. ¹H NMR (500 MHz, DMSO-d₆) δ 10.86(br. s., 1H), 7.67 (br. s., 1H), 7.48 (br. s., 1H), 7.34 (br. s., 1H),7.25 (d, J=8.0 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 3.17 (br. s., 2H),3.12-3.03 (m, 1H), 2.75 (d, J=11.6 Hz, 3H), 1.83 (br. s., 6H), 1.75 (d,J=13.9 Hz, 3H), 1.40 (d, J=6.6 Hz, 6H), 1.16 (d, J=6.6 Hz, 6H).

EXAMPLE 673-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one

Intermediate 67A: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(1-methyl-6-oxo-5-vinyl-1,6-dihydropyridin-3-yl)-1H-indole-1-carboxylate

Intermediate 67A was prepared according to the general procedure forIntermediate 66B substituting4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane for4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane.tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(1-methyl-6-oxo-5-vinyl-1,6-dihydropyridin-3-yl)-1H-indole-1-carboxylate(85.3 mg, 0.126 mmol, 72% yield, 85% purity) was obtained as a clear,pale yellow oil. LCMS MH⁺: 576.3. HPLC Ret. Time 1.24 min. Method B1. ¹HNMR (400 MHz, CHLOROFORM-d) δ 8.19 (d, J=8.7 Hz, 1H), 7.54 (d, J=1.5 Hz,1H), 7.38 (d, J=2.3 Hz, 1H), 7.24-7.19 (m, 2H), 6.89 (dd, J=17.7, 11.4Hz, 1H), 6.06 (dd, J=17.7, 1.5 Hz, 1H), 5.39 (dd, J=11.2, 1.3 Hz, 1H),4.35-4.26 (m, 2H), 3.65 (s, 3H), 3.00 (dquin, J=14.2, 7.1 Hz, 1H), 2.86(t, J=12.2 Hz, 2H), 2.81-2.74 (m, 1H), 1.90 (d, J=12.3 Hz, 2H), 1.71(qd, J=12.5, 3.5 Hz, 2H), 1.51 (s, 9H), 1.40 (s, 9H), 1.38 (d, J=7.2 Hz,6H).

EXAMPLE 67

5% Pd on carbon (30 mg, 0.148 mmol) was weighed into a 2-dram vial.tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(1-methyl-6-oxo-5-vinyl-1,6-dihydropyridin-3-yl)-1H-indole-1-carboxylate(85.3 mg, 0.148 mmol) was dissolved in MeOH (1.482 mL) and transferredinto the vial containing the Pd on C while under a nitrogen atmosphere.Ammonium formate (74.7 mg, 1.185 mmol) was added to the reactionmixture. The vial was placed under a nitrogen atmosphere. The reactionmixture was stirred at 60° C. for 2 h. The reaction mixture was filteredthrough celite, flushing with MeOH. Excess solvent was evaporated fromthe reaction mixture.

The resulting residue was partitioned between DCM and water (1:1, 5 mLtotal volume), the phases were separated, and the aqueous phase wasextracted with DCM (2×1 mL). Excess solvent was evaporated from thecombined organic phases. The resulting residue was taken up in DCM andpurified by flash chromatography on a 4 g silica column, eluting withethyl acetate and hexanes to afford tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-ethyl-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indole-1-carboxylate(50.4 mg, 0.079 mmol, 53.0% yield) as a white solid. This wasBoc-deprotected by reacting with 2:1 trifluoroaceticacid/dichloromethane (1.2 mL, 0.044 mmol) in a 1-dram vial for 50 min.Toluene (˜0.15 mL) was added, and excess solvent was then evaporatedfrom the reaction. DMF (˜1.5 mL) was added to the resulting residue, andthe crude material was purified via preparative LC/MS. Fractionscontaining the product were combined and dried via centrifugalevaporation to afford3-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(4.0 mg, 10.6 μmol, 24% yield, 100% purity). LCMS MH⁺: 378.1. HPLC Ret.Time 1.15 min. Method QC-ACN-TFA-XB. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81(s, 1H), 7.65 (s, 1H), 7.47 (s, 1H), 7.37 (br. s., 1H), 7.24 (d, J=8.2Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 3.53 (s, 2H), 3.47 (br. s., 1H),3.20-3.08 (m, 3H), 2.71 (d, J=10.7 Hz, 3H), 1.82 (br. s., 3H), 1.78 (br.s., 2H), 1.67 (d, J=12.2 Hz, 2H), 1.39 (d, J=6.7 Hz, 6H), 1.14 (t, J=7.5Hz, 3H).

EXAMPLE 681,3-diethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)pyridin-2(1H)-one

Intermediate 68A:tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indole-1-carboxylate

5-bromo-3-chloro-1-ethylpyridin-2(1H)-one (F-28) 0.058 g, 0.246 mmol)was coupled to tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(0.140 g, 0.246 mmol) as described above for Example 2. Obtainedtert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indole-1-carboxylate(120.6 mg, 0.192 mmol, 78% yield) as a yellow foam. LCMS MH⁺: 598.2.HPLC Ret. Time 1.24 min. Method B1. ¹H NMR (400 MHz, CHLOROFORM-d) δ8.21 (s, 1H), 8.19 (s, 1H), 7.61 (d, J=2.6 Hz, 1H), 7.54 (d, J=1.6 Hz,1H), 7.48 (d, J=2.3 Hz, 1H), 7.39 (d, J=2.6 Hz, 1H), 7.23 (dd, J=8.7,1.7 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 4.30 (d, J=9.7 Hz, 2H), 4.14 (quin,J=6.9 Hz, 1H), 4.05 (q, J=7.2 Hz, 1H), 2.99 (quin, J=7.2 Hz, 1H), 2.87(t, J=12.3 Hz, 2H), 2.79 (tt, J=12.1, 3.4 Hz, 1H), 1.91 (d, J=12.3 Hz,2H), 1.72 (qd, J=12.3, 3.8 Hz, 2H), 1.54-1.51 (m, 9H), 1.45 (s, 9H),1.43-1.40 (m, 2H), 1.39 (d, J=7.1 Hz, 6H).

Intermediate 68B: tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(1-ethyl-6-oxo-5-vinyl-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indole-1-carboxylate

tert-Butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indole-1-carboxylate(45 mg, 0.075 mmol) was coupled to4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (31.9 0.188 mmol) asaccording to the general procedure for Intermediate 66B. Obtainedtert-butyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(1-ethyl-6-oxo-5-vinyl-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indole-1-carboxylate(43.6 mg, 0.055 mmol, 73.7% yield) as a pale yellow oil. LCMS MH⁺:590.3. HPLC Ret. Time 1.26 min. Method B1.

EXAMPLE 68

tert-Butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(1-ethyl-6-oxo-5-vinyl-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indole-1-carboxylate(26 mg, 0.044 mmol) was reduced and deprotected according to the generalprocedure for Example 66. Obtained1,3-diethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)pyridin-2(1H)-one(4.0 mg, 9.81 μmol, 22% yield, 96% purity). LCMS MH⁺: 392.1. HPLC Ret.Time 1.34 min. QC-ACN-TFA-XB. ¹H NMR (500 MHz, DMSO-d₆) δ 10.84 (s, 1H),7.71-7.60 (m, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.25 (d, J=8.2 Hz, 1H),6.95 (d, J=8.4 Hz, 1H), 4.02 (q, J=6.9 Hz, 2H), 3.15 (dd, J=14.4, 7.2Hz, 2H), 2.70 (br. s., 2H), 1.84 (br. s., 4H), 1.76 (br. s., 2H), 1.68(br. s., 2H), 1.41 (d, J=7.0 Hz, 6H), 1.28 (t, J=7.1 Hz, 3H), 1.15 (t,J=7.4 Hz, 3H).

EXAMPLE 69 5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrrolidine-1-carbonyl) pyridin-2(1H)-one

Intermediate 69A: Methyl5-(5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate

Methyl 5 -bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (111mg, 0.451 mmol) and tert-butyl4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate(176 mg, 0.376 mmol) were coupled according to the general procedure forExample 1. Obtained methyl5-(5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate(141.1 mg, 0.250 mmol, 66.6% yield) as an orange solid. LCMS MH⁺: 508.3.HPLC Ret. Time 1.04 min. Method B1. ¹H NMR (400 MHz, CHLOROFORM-d) δ8.38 (s, 1H), 8.24 (d, J=2.7 Hz, 1H), 7.63 (d, J=2.7 Hz, 1H), 7.59 (s,1H), 7.36 (d, J=8.4 Hz, 1H), 7.09 (dd, J=8.4, 1.6 Hz, 1H), 4.38-4.22 (m,2H), 3.88 (s, 3H), 3.67 (s, 3H), 3.14 (spt, J=7.0 Hz, 1H), 2.87 (t,J=12.3 Hz, 2H), 2.77 (tt, J=12.1, 3.4 Hz, 1H), 1.96-1.87 (m, 2H), 1.73(qd, J=12.6, 3.8 Hz, 2H), 1.52 (s, 9H), 1.47 (d, J=7.1 Hz, 6H).

Intermediate 69B:5-(5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylicacid

Methyl5-(5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate(50 mg, 0.098 mmol) was suspended in MeOH (1 mL) in a 1-dram vial.Sodium hydroxide (0.197 mL, 0.197 mmol) was added to the vial, and thevial was capped. The reaction mixture was stirred at 65° C. for 1.5 h.Water (0.5 mL), IN aqueous HCl (210 μL), ethyl acetate (1.5 mL) andbrine solution (0.5 mL) were added to the reaction mixture, resulting indissolution of the solid and formation of 2 layers (a colorless aqueouslayer and a yellow organic layer). The phases were separated, and theaqueous layer was extracted with ethyl acetate (2×2 mL). The combinedorganic extracts were dried over sodium sulfate, then filtered, andexcess solvent was evaporated off to afford5-(5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylicacid (50.3 mg, 0.097 mmol, 98% yield) as a yellow solid. LCMS MH⁺:494.4. HPLC Ret. Time 1.06 min. Method B1.

EXAMPLE 69

PyBOP (19.45 mg, 0.037 mmol), DIEA (10.88 μl, 0.062 mmol), and5-(5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylicacid (12.3 mg, 0.025 mmol) were combined in DMF (500 μL) in a 1-dramvial and stirred for 10 min. Pyrrolidine (5.20 82 l, 0.062 mmol) wasthen added to the reaction mixture. The reaction mixture was stirred atroom temperature for 2 h. The reaction mixture was partitioned betweenwater and ethyl acetate (3 mL total volume), separated, and the aqueousphase was extracted with additional ethyl acetate (2×1 mL). Excesssolvent was evaporated from the combined organic extracts. The resultingresidue was deprotected with 2:1 trifluoroacetic acid/dichloromethane(1.2 mL, 0.025 mmol) for 45 min. Excess solvent was evaporated from thereaction mixture. The crude material was dissolved in DMF (1.5 mL) andpurified via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-ìm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-45% B over20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the product were combined and dried via centrifugalevaporation. The material was further purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-ìmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: 7-47% B over 25 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the product werecombined and dried via centrifugal evaporation to afford5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrrolidine-1-carbonyl)pyridin-2(1H)-one(7.5 mg, 66% yield, 99% purity). LCMS MH⁺: 447.2. HPLC Ret. Time 1.13min. Method QC-ACN-TFA-XB. ¹H NMR (500 MHz, DMSO-d₆) δ 10.76 (s, 1H),7.71 (s, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.31 (s, 1H), 7.09 (d, J=4.5 Hz,1H), 6.77 (d, J=8.2 Hz, 1H), 3.39 (br. s., 3H), 3.26-3.15 (m, 3H),3.14-3.09 (m, 2H), 3.01-2.91 (m, 1H), 2.88-2.78 (m, 2H), 2.70 (s, 2H),1.82-1.73 (m, 2H), 1.69-1.57 (m, 7H), 1.20 (d, J=7.0 Hz, 6H).

EXAMPLE 703-(hydroxymethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one

Intermediate 70A: 5-bromo-3-(hydroxymethyl)pyridin-2(1H)-one

Methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (Combi-Blocks,CAS: 120034-05-1, 0.100 g, 0.431 mmol) was dissolved in THF (4.31 mL)and added dropwise to a 0° C. solution of lithium aluminum hydride(0.082 g, 2.155 mmol) in THF (4.31 mL). The reaction mixture was stirredat 0° C. for 30 min, then allowed to warm to room temperature andstirred for 2.5 h. Saturated aqueous NH₄Cl solution (8 mL) was slowlyadded to the reaction mixture, followed by ethyl acetate (8 mL). Thephases were separated, the aqueous phase was extracted with additionalethyl acetate (2×10 mL). The combined organic phases were dried oversodium sulfate and filtered, and excess solvent was evaporated off toafford 5-bromo-3-(hydroxymethyl)pyridin-2(1H)-one (34.1 mg, 0.159 mmol,36.8% yield) as a white solid. LCMS MH⁺: 203.9. HPLC Ret. Time 0.47 min.Method B1. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.67 (dt, J=2.7, 1.4 Hz, 1H),7.51 (d, J=2.7 Hz, 1H), 4.49 (s, 2H).

Intermediate 70B: 5-bromo-3-(hydroxymethyl)-1-methylpyridin-2(1H)-one

5-bromo-3-(hydroxymethyl)pyridin-2(1H)-one (34.1 mg, 0.167 mmol) wasstirred with iodomethane (30.5 μl, 0.201 mmol) and potassium carbonate(115 mg, 0.836 mmol) in DMF (557 μl) in a 2-dram vial containing aTeflon-coated stir bar at room temperature for 1 h. Additional DMF (1.0mL) was added to the reaction mixture. The reaction mixture was stirredat room temperature for 19 h. The reaction mixture was partitionedbetween water and ethyl acetate (˜4 mL total volume), and the aqueousphase was extracted with ethyl acetate (3×2.5 mL). The combined organicphases were extracted with brine (2×2 mL), then dried over sodiumsulfate and filtered. Excess solvent was evaporated from the filteredorganic phase to afford5-bromo-3-(hydroxymethyl)-1-methylpyridin-2(1H)-one (17.7 mg, 0.073mmol, 43.7% yield) as a clear, pale yellow oil. LCMS MH⁺: 217.9. HPLCRet. Time 0.51 min. Method B1. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.42 (s,2H), 4.57 (d, J=6.2 Hz, 2H), 3.56 (s, 3H), 3.41 (t, J=6.4 Hz, 1H).

EXAMPLE 70

5-bromo-3-(hydroxymethyl)-1-methylpyridin-2(1H)-one was coupled totert-butyl4-(3-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-5-yl)piperidine-1-carboxylate and deprotected according to the generalprocedure for Example 1 to afford3-(hydroxymethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(21.9 mg, 70% yield, 98% purity). LCMS MH⁺: 380.4. HPLC Ret. Time 0.82min. Method QC-ACN-TFA-XB. ¹H NMR (500 MHz, DMSO-d₆) δ 10.71 (s, 1H),7.51 (s, 1H), 7.40 (br. s., 1H), 7.31 (s, 1H), 7.09 (d, J=8.2 Hz, 1H),6.78 (d, J=8.2 Hz, 1H), 4.21 (s, 2H), 3.55 (br. s., 4H), 3.36 (s, 2H),3.11 (d, J=10.3 Hz, 1H), 2.99 (quin, J=6.9 Hz, 1H), 2.72 (d, J=11.2 Hz,2H), 2.64 (br. s., 1H), 1.75-1.68 (m, 2H), 1.67-1.56 (m, 2H), 1.20 (d,J=6.9 Hz, 6H).

EXAMPLE 712-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide

-   Method A: A mixture containing    5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one    (75 mg, 0.206 mmol), 2-chloro-N,N-dimethylacetamide (0.027 mL, 0.258    mmol) and K₂CO₃ (86 mg, 0.619 mmol) was suspended in DMF (0.5 mL).    The reaction mixture was stirred at room temperature for 4 h. The    reaction mixture was treated with water (4 mL) and stirred for 30    min. The resulting solids were filtered and rinsed with water and    diethylether, and dried to afford    2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide    (70 mg, 0.148 mmol, 71.8% yield), as a white solid. m/e (449, M⁺¹).    LCMS MH⁺: 449.5. HPLC Ret. Time 0.64 min. Method B1. ¹H NMR (400    MHz, DMSO-d₆) δ 10.77 (s, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.48 (s, 1H),    7.45-7.40 (m, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.96 (dd, J=8.4, 1.4 Hz,    1H), 3.54 (s, 3H), 3.21-3.11 (m, 3H), 3.08 (s, 3H), 2.95 (d, J=11.1    Hz, 2H), 2.83 (s, 3H), 2.23-2.12 (m, 2H), 2.09 (s, 3H), 1.84-1.63    (m, 4H), 1.40 (d, J=7.0 Hz, 6H).

The following examples were prepared according to the general procedurefor Example 71 using the indicated starting material.

TABLE 4 Ret Ex. Starting LCMS Time HPLC No. Structure material MH⁺ (min)Method 72

Ex-2 459.4 0.63 Method B1 73

Ex-14 464 1.33 QC-ACN-AA-XB 74

Ex-3 464 1.27 QC-ACN-AA-XB 75

Ex-2 420 1.33 QC-ACN-TFA-XB 76

Ex-2 417 1.67 QC-ACN-AA-XB 77

Ex-2 538 2.35 QC-ACN-AA-XB 78

Ex-2 538 2.28 QC-ACN-AA-XB 79

Ex-2 474 1.69 QC-ACN-AA-XB 80

Ex-2 506 2.49 QC-ACN-AA-XB 81

Ex-2 482 1.51 QC-ACN-AA-XB 82

Ex-2 435 1.05 QC-ACN-AA-XB 83

Ex-2 454 1.31 QC-ACN-TFA-XB 84

Ex-2 489 1.14 QC-ACN-TFA-XB 85

Ex-2 422 1.09 QC-ACN-AA-XB 86

Ex-2 434 1.6 QC-ACN-TFA-XB 87

Ex-2 446 1.47 QC-ACN-TFA-XB 88

Ex-2 542 2.47 QC-ACN-AA-XB 89

Ex-50 483 1.06 QC-ACN-TFA-XB 90

Ex-50 497 1.27 QC-ACN-TFA-XB 91

Ex-31 468 1.63 QC-ACN-AA-XB 92

Ex-31 468 1.32 QC-ACN-AA-XB 93

Ex-31 496 1.32 QC-ACN-TFA-XB 94

Ex-54 498 1.32 QC-ACN-AA-XB 95

Ex-31 456 1.42 QC-ACN-AA-XB 96

Ex-31 437 1.89 QC-ACN-AA-XB 97

Ex-31 466 1.48 QC-ACN-AA-XB 98

Ex-31 544 1.5 QC-ACN-AA-XB 99

Ex-31 470 1.32 QC-ACN-AA-XB 100

Ex-54 526 1.16 QC-ACN-TFA-XB 101

Ex-31 500 1.46 QC-ACN-AA-XB 102

Ex-31 494 2.04 QC-ACN-AA-XB 103

Ex-54 486 1.23 QC-ACN-TFA-XB 104

Ex-54 538 1.46 QC-ACN-AA-XB 105

508.02 508 1.97 QC-ACN-AA-XB 106

Ex-31 454 1.59 QC-ACN-AA-XB 107

Ex-31 504 1.55 QC-ACN-AA-XB 108

Ex-54 535 1.0 QC-ACN-TFA-XB 109

Ex-39 464 1.65 QC-ACN-AA-XB 110

Ex-36 516 1.99 QC-ACN-AA-XB 111

Ex-46 550 2.02 QC-ACN-AA-XB 112

Ex-36 462 1.77 QC-ACN-AA-XB 113

Ex-46 496.2 1.82 QC-ACN-AA-XB 114

Ex-1 435.1 1.13 QC-ACN-AA-XB 115

Ex-12 450.2 1.26 QC-ACN-AA-XB 116

Ex-11 450 1.21 QC-ACN-AA-XB 117

Ex-2 435.3 0.63 Method B1 118

Ex-11 436.3 0.65 Method B1 119

Ex-2 491.4 1.07 QC-ACN-TFA-XB 120

Ex-2 491.4 0.62 Method B1 121

Ex-2 490 1.15 QC-ACN-AA-XB 122

Ex-2 475.3 1.18 QC-ACN-TFA-XB 123

Ex-2 447.3 0.62 Method B1 124

Ex-2 493 1.05 QC-ACN-TFA-XB 125

Ex-2 479.3 1.06 QC-ACN-TFA-XB 126

Ex-2 479 1 QC-ACN-TFA-XB 127

Ex-2 461.2 1.11 QC-ACN-TFA-XB 128

Ex-20 465.3 0.61 Method B1 129

Ex-20 451.3 0.59 Method B1 130

Ex-17 464.3 0.67 Method B1 131

Ex-17 450.3 0.65- QC-ACN-TFA-XB 132

Ex-15 449 1.72 Method B1 133

Ex-15 463.4 1.47 Method B1 134

Ex-14 463.3 0.67 Method B1 135

Ex-14 449.3 0.64 Method B1 136

Ex-26 477.3 0.70 Method B1 137

Ex-26 463.3 0.68 Method B1 138

Ex-3 463.3 0.67 Method B1 139

Ex-3 449.3 0.65 Method B1 140

Ex-29 465.3 0.63 Method B1 141

Ex-29 479.3 0.64 Method B1 142

Ex-28 465.2 0.62 Method B1 143

Ex-28 479.2 0.64 Method B1 144

Ex-23 460.3 0.64 Method B1 145

Ex-23 474.3 0.65 Method B1 146

Ex-24 460.3 0.64 Method B1 147

Ex-24 474.3 0.66 Method B1 148

Ex-2 450.3 1.05 QC-ACN-AA-XB 149

Ex-2 462 1.75 QC-ACN-AA-XB 150

Ex-2 421.3 1.35 QC-ACN-AA-XB 151

Ex-2 449 1.62 QC-ACN-AA-XB 152

Ex-31 483.3 1.24 QC-ACN-TFA-XB 153

Ex-31 469 1.25 QC-ACN-TFA-XB 154

Ex-31 483.4 1.76 QC-ACN-AA-XB 155

Ex-31 483 1.36 QC-ACN-TFA-XB 156

Ex-31 469 1.64 QC-ACN-AA-XB 157

Ex-31 469 1.18 QC-ACN-AA-XB 158

Ex-31 501 1.39 QC-ACN-AA-XB 159

Ex-39 493.4 1.46 QC-ACN-AA-XB 160

Ex-39 479.1 1.28 QC-ACN-TFA-XB 161

Ex-36 477.5 1.75 QC-ACN-AA-XB 162

Ex-46 511.5 1.8 QC-ACN-AA-XB 163

Ex-36 491.5 1.55 QC-ACN-AA-XB 164

Ex-46 525 1.45 QC-ACN-TFA-XB 165

Ex-45 517.1 1.47 QC-ACN-AA-XB 166

Ex-40 499.2 1.33 QC-ACN-TFA-XB 167

Ex-30 479.1 1.06 QC-ACN-TFA-XB 168

Ex-67 463.12 1.37 QC-ACN-TFA-XB 169

Ex-50 512 1.4 QC-ACN-AA-XB 170

Ex-53 511 1.87 QC-ACN-AA-XB

EXAMPLE 1715-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one

-   General Method 1: A mixture containing    5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one    (100 mg, 0.275 mmol), oxetan-3-one (99 mg, 1.376 mmol) and sodium    triacetoxyborohydride (233 mg, 1.100 mmol) was suspended in DMF (1    mL) followed by the addition of acetic acid (0.025 mL, 0.437 mmol).    The reaction mixture was stirred for 20 h. The reaction mixture was    treated with concentrated aqueous ammonium hydroxide (7 mL) and the    resulting solids were stirred and sonicated periodically for 30 min.    The resulting suspension was filtered, rinsed with additional    ammonium hydroxide and dried to afford    5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one    (55 mg, 0.125 mmol, 45.3%yield), ˜95% pure. m/z (420, M⁺¹). LCMS    MH⁺: 420.2. HPLC Ret. Time 0.61 min. Method B. ¹H NMR (400 MHz,    METHANOL-d₄) δ 7.63 (d, J=2.3 Hz, 1H), 7.58 (s, 2H), 7.28 (d, J=8.3    Hz, 1H), 7.03 (dd, J=8.4, 1.5 Hz, 1H), 4.77-4.71 (m, 2H), 4.71-4.66    (m, 2H), 3.68 (s, 3H), 3.58 (quin, J=6.5 Hz, 1H), 3.26-3.19 (m, 1H),    2.96 (d, J=11.4 Hz, 2H), 2.65 (td, J=10.4, 5.3 Hz, 1H), 2.22 (s,    3H), 2.10-2.01 (m, 2H), 1.97-1.86 (m, 4H), 1.48 (d, J=7.0 Hz, 6H).

EXAMPLE 1725-(3-isopropyl-5-(1-(2-(methylamino)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one

-   General Method 2: To a solution containing    5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one,    HCl (30 mg, 0.078 mmol), Example 1, and tert-butyl    methyl(2-oxoethyl)carbamate (26.9 mg, 0.155 mmol) in THF (1 mL) was    added TEA (10.83 82 l, 0.078 mmol) followed by the addition of    sodium triacetoxyborohydride (65.9 mg, 0.311 mmol) and a drop of    acetic acid. The reaction mixture was stirred for 20 h, diluted with    ethyl acetate (5 mL) and washed with aqueous 1N NaOH (2×2 mL) and    saturated aqueous NaCl solution (1×1 mL), filtered through a plug of    Na₂SO₄ and concentrated. The residue was dissolved in DCM (1 mL) and    treated with TFA (0.5 mL). The reaction mixture was concentrated.    The sample was dissolved in DMF (2 mL), filtered through an    Acrodisc, 13 mm, 0.45 micron nylon membrane syringe filter. The    crude material was purified via preparative LC/MS. Fractions    containing the product were combined and dried via centrifugal    evaporation to afford    5-(3-isopropyl-5-(1-(2-(methylamino)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one    (18.5 mg, 0.046 mmol, 58.5% yield). LCMS MH⁺: 407. HPLC Ret. Time    0.79 min. Method B. ¹H NMR (500 MHz, DMSO-d₆) δ 10.83 (s, 1H), 7.81    (d, J=2.1 Hz, 1H), 7.54 (dd, J=9.3, 2.3 Hz, 1H), 7.50-7.45 (m, 1H),    7.26-7.21 (m, 1H), 6.99-6.94 (m, 1H), 6.56-6.49 (m, 1H), 3.20-3.10    (m, 1H), 2.98 (br d, J=10.9 Hz, 2H), 2.77-2.72 (m, 2H), 2.55 (s,    3H), 2.47 (br t, J=6.2 Hz, 2H), 2.40 (s, 3H), 2.06 (br t, J=10.5 Hz,    2H), 1.87 (s, 1H), 1.81-1.67 (m, 4H), 1.40 (d, J=7.0 Hz, 6H).

EXAMPLE 1735-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(piperidin-1-yl)pyridin-2(1H)-one

A mixture of tert-butyl5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indole-1-carboxylate(20 mg, 0.034 mmol), piperidine (10.15 82 l, 0.103 mmol), Xantphos (2.97mg, 5.14 μmol), Pd₂(dba)₃ (2.351 mg, 2.57 μmol), and Cs₂CO₃ (44.6 mg,0.137 mmol) in dioxane (1.0 mL) was purged with nitrogen for 2 min. andthen stirred at 130° C. The reaction mixture was cooled to roomtemperature and checked by LCMS. The product m/z (633.3, M+H) wasobserved. The reaction mixture was partitioned between water and ethylacetate (1:1, 3 mL total volume), and the phases were separated. Theaqueous phase was extracted with ethyl acetate (2×1 mL), and excesssolvent was evaporated from the combined organic phases. The resultingresidue was Boc-deprotected with 2:1 trifluoroaceticacid/dichloromethane (1.2 mL, 0.034 mmol), stirring at room temperaturefor 30 min. Toluene (˜150 μL) was added to the reaction mixture, andconcentrated to dryness. The residue was taken up in DMF (˜1.8 mL) andpurified by preparative LCMS to afford5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(piperidin-1-yl)pyridin-2(1H)-one, TFA (12.3 mg, 0.011 mmol, 32.9% yield) as a greenishoil. DMF (225 μl) was added to5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(piperidin-1-yl)pyridin-2(1H)-one,TFA (12.3 mg, 0.023 mmol) in a 1-dram vial, followed by DIEA (9.82 82 l,0.056 mmol) and propionaldehyde (16.38 82 l, 0.225 mmol). The reactionmixture was stirred at room temperature for 5 min, then acetic acid(7.73 82 l, 0.135 mmol) and sodium triacetoxyborohydride (47.7 mg, 0.225mmol) were added. The reaction mixture was stirred at room temperaturefor 2 h, diluted with MeOH (1 mL) and subjected to HPLC purification toafford5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(piperidin-1-yl)pyridin-2(1H)-one,(0.7 mg, 7%). LCMS MH⁺: 475. HPLC Ret. Time 1.76 min. MethodQC-ACN-AA-XB.

The following examples were prepared according to the general proceduresfor Examples 171-173, using the indicated starting material.

TABLE 5 Ret Ex. Starting LCMS Time HPLC No. Structure Material MH⁺ (min)Method 174

Ex-31 495 1.64 QC-ACN-AA-XB 175

Ex-1 406 1.44 QC-ACN-AA-XB 176

Ex-2 421 1.26 QC-ACN-AA-XB 177

Ex-1 420 1.28 QC-ACN-AA-XB 178

Ex-2 448 1.3 QC-ACN-AA-XB 179

Ex-1 434 1.17 QC-ACN-AA-XB 180

Ex-2 434 1.42 QC-ACN-AA-XB 181

Ex-2 378 1.11 QC-ACN-AA-XB 182

Ex-2 406 1.37 QC-ACN-AA-XB 183

Ex-12 379 1.1 QC-ACN-TFA-XB 184

Ex-12 407 1.25 QC-ACN-TFA-XB 185

Ex-12 449 1.24 QC-ACN-AA-XB 186

Ex-12 421 1.57 QC-ACN-AA-XB 187

Ex-12 449 1.22 QC-ACN-TFA-XB 188

Ex-11 449 1.53 QC-ACN-AA-XB 189

Ex-11 421 1.65 QC-ACN-AA-XB 190

Ex-12 435 1.07 QC-ACN-TFA-XB 191

Ex-11 379 1.15 QC-ACN-AA-XB 192

Ex-11 407 1.25 QC-ACN-TFA-XB 193

Ex-11 435 1.53 QC-ACN-AA-XB 194

Ex-11 897 1.18 QC-ACN-TFA-XB 195

Ex-2 458 1.3 QC-ACN-AA-XB 196

Ex-2 458 1.22 QC-ACN-AA-XB 197

Ex-2 458 1.76 QC-ACN-AA-XB 198

Ex-2 459 1.52 QC-ACN-AA-XB 199

Ex-2 482.4 0.73 Method B1 200

Ex-2 444 1.1 QC-ACN-TFA-XB 201

Ex-20 464.3 0.62 Method B1 202

Ex-20 436.3 0.59 Method B1 203

Ex-17 435.3 0.65 Method B1 204

Ex-15 434 1.77 QC-ACN-AA-XB 205

Ex-17 463 1.45 QC-ACN-AA-XB 206

Ex-14 462 1.2 QC-ACN-AA-XB 207

Ex-14 434 1.33 QC-ACN-TFA-XB 208

Ex-26 476 1.36 QC-ACN-AA-XB 209

Ex-26 448 1.75 QC-ACN-AA-XB 210

Ex-3 462 1.21 QC-ACN-TFA-XB 211

Ex-3 434 1.58 QC-ACN-AA-XB 212

Ex-14 420.1 0.69 Method B1 213

Ex-26 434.3 0.73 Method B1 214

Ex-3 420.3 0.70 Method B1 215

Ex-29 450.3 0.62 Method B1 216

Ex-29 478.3 0.66 Method B1 217

Ex-28 450.2 0.62 Method B1 218

Ex-28 478.2 0.65 Method B1 219

Ex-23 445.0 0.63 Method B1 220

Ex-23 473.1 0.67 Method B1 221

Ex-24 445.1 0.63 Method B1 222

Ex-24 473.1 0.67 Method B1 223

Ex-2 418.3 1.25 QC-ACN-TFA-XB 224

Ex-2 406 1.3 QC-ACN-AA-XB 225

Ex-2 448 1.34 QC-ACN-AA-XB 226

Ex-22 468 1.19 QC-ACN-TFA-XB 227

Ex-2 486 1.4 QC-ACN-AA-XB 228

Ex-2 486 1.45 QC-ACN-AA-XB 229

Ex-2 503 1.15 QC-ACN-TFA-XB 230

Ex-2 514 1.8 QC-ACN-AA-XB 231

Ex-2 514 1.56 QC-ACN-TFA-XB 232

Ex-2 472 1.31 QC-ACN-AA-XB 233

Ex-2 488 1.78 QC-ACN-TFA-XB 234

Ex-2 488 1.98 QC-ACN-AA-XB 235

Ex-50 469 1.11 QC-ACN-TFA-XB 236

Ex-50 471 0.97 QC-ACN-TFA-XB 237

Ex-50 483 1.21 QC-ACN-AA-XB 238

Ex-31 440 1.31 QC-ACN-AA-XB 239

Ex-31 482 1.26 QC-ACN-TFA-XB 240

Ex-31 412 1.19 QC-ACN-TFA-XB 241

Ex-31 523.3 1.2 QC-ACN-AA-XB 242

Ex-31 440 1.48 QC-ACN-AA-XB 243

Ex-31 500.4 1.25 QC-ACN-AA-XB 244

Ex-54 470 1.16 QC-ACN-TFA-XB 245

Ex-50 469 1.28 QC-ACN-AA-XB 246

Ex-54 442 1.14 QC-ACN-AA-XB 247

Ex-50 441 0.85 QC-ACN-TFA-XB 248

Ex-31 454 1.75 QC-ACN-AA-XB 249

Ex-54 470 1.17 QC-ACN-AA-XB 250

Ex-31 482 1.4 QC-ACN-AA-XB 251

Ex-31 454 1.51 QC-ACN-TFA-XB 252

Ex-31 482 1.26 QC-ACN-TFA-XB 253

Ex-31 472 1.25 QC-ACN-TFA-XB 254

Ex-31 482.3 0.73 QC-ACN-TFA-XB 255

Ex-31 482.3 0.73 QC-ACN-TFA-XB 256

Ex-54 484 1.26 QC-ACN-AA-XB 257

Ex-54 512 1.17 QC-ACN-AA-XB 258

Ex-54 489 1.28 QC-ACN-AA-XB 259

Ex-54 531 1.21 QC-ACN-AA-XB 260

Ex-54 485 1.22 QC-ACN-AA-XB 261

Ex-39 492.5 1.29 QC-ACN-AA-XB 262

Ex-36 490.1 1.54 QC-ACN-AA-XB 263

Ex-46 524 1.66 QC-ACN-AA-XB 264

Ex-30 408 1.05 QC-ACN-TFA-XB 265

Ex-45 446 1.39 QC-ACN-AA-XB 266

Ex-40 428 1.24 QC-ACN-AA-XB 267

Ex-2 504 1.33 QC-ACN-TFA-XB 268

Ex-2 504 1.46 QC-ACN-TFA-XB 269

Ex-2 472 1.17 QC-ACN-TFA-XB 270

Ex-2 504.2 1.37 QC-ACN-AA-XB

EXAMPLE 2715-(5-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one

-   General Method C: A mixture containing 2-(dimethylamino)acetic acid    (12.38 mg, 0.120 mmol),    5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one,    HCl (32 mg, 0.080 mmol), and HCTU (49.6 mg, 0.120 mmol) was    suspended in THF (1 mL), followed by the addition of TEA (0.045 mL,    0.32 mmol). The reaction mixture was stirred for 7 h and    concentrated to dryness under a stream of nitrogen. The residue was    suspended in aqueous 0.1 N NaOH (5 mL) and stirred for 30 min. The    solids were filtered, rinsed sequentially with additional 0.1 N NaOH    and water, and dried to afford    5-(5-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one    (35 mg, 0.074 mmol, 93% yield). LCMS MEV: 449.2. HPLC Ret. Time 0.67    min. Method B1. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.91-7.86 (m, 1H),    7.61-7.57 (m, 1H), 7.36-7.30 (m, 2H), 7.06 (dd, J=8.4, 1.5 Hz, 1H),    4.81 (br d, J=13.5 Hz, 1H), 4.27 (br d, J=13.5 Hz, 1H), 3.64 (s,    3H), 3.26-3.13 (m, 1H), 2.93-2.84 (m, 1H), 2.84-2.80 (s, 2H),    2.76-2.67 (m, 1H), 2.35 (s, 6H, 2.24 (s, 3H), 1.99 (br m, J=12.7 Hz,    1H), 1.81-1.59 (m, 4H), 1.47 (d, J=7.0 Hz, 6H).

EXAMPLE 2725-(5-(1-(1-aminocyclopropanecarbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one

A mixture containing1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (15.3 mg,0.075 mmol),5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one,HCl (20 mg, 0.050 mmol), and HCTU (31.0 mg, 0.075 mmol) was suspended inTHF (0.5 mL) and TEA (0.035 mL, 0.250 mmol) was added. The reactionmixture was stirred for 20 h, diluted with ethyl acetate (4 mL) andwashed with 1N NaOH (2×1 mL) and saturated aqueous NaCl solution (1 mL)and concentrated. The residue was treated with TFA (1 mL) for 30 min tofacilitate the removal of the Boc groups. The reaction mixture wasre-concentrated to dryness and re-dissolved in DMF (2 mL). The samplewas filtered through an Acrodisc, 13 mm, 0.45 micron nylon membranesyringe filter. The crude material was purified via preparative LC/MS.Fractions containing the product were combined and dried via centrifugalevaporation to afford5-(5-(1-(1-aminocyclopropanecarbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(2.6 mg, 12%). LCMS MH⁺: 449.2. HPLC Ret. Time 1.21 min.Method-QC-ACN-AA-XB. ¹H NMR (500 MHz, DMSO-d₆) δ 10.79 (s, 1H),7.66-7.59 (m, 1H), 7.47 (s, 1H), 7.43 (br s, 1H), 7.23 (br d, J=8.3 Hz,1H), 6.95 (br d, J=8.2 Hz, 1H), 4.44 (br d, J=12.5 Hz, 2H), 3.66-3.59(m, 3H), 3.19-3.09 (m, 2H), 2.90-2.71 (m, 2H), 2.54 (s, 1H), 2.07 (s,3H), 1.86-1.75 (m, 3H), 1.69-1.48 (m, 2H), 1.37 (br d, J=6.8 Hz, 6H),0.83 (br s, 2H), 0.67 (br s, 2H).

The following examples were prepared according to the general method forExamples 271 or Example 272, using the indicated starting material.

TABLE 6 Ret Ex. Starting LCMS Time HPLC No. Structure Material MH⁺ (min)Method 273

Ex-23 473.9 1.33 QC- ACN- AA- XB 274

Ex-24 474.2 1.36 QC- ACN- AA- XB 275

Ex-28 479.2 0.65 QC- ACN- TFA- XB 276

Ex-29 479.1 1.18 QC- ACN- AA- XB 277

Ex-353 479.4 1.29 QC- ACN- TFA- XB 278

Ex-31 483 1.54 QC- ACN- AA- XB 279

Ex-3 463.4 1.28 QC- ACN- AA- XB 280

Ex-14 463.2 1.44 QC- ACN- AA- XB 281

Ex-26 477.1 1.3 QC- ACN- AA- XB 282

Ex-15 463.2 1.45 QC- ACN- AA- XB 283

Ex-17 464.4 0.69 QC- ACN- TFA- XB 284

Ex-46 525.6 1.66 QC- ACN- AA- XB 285

Ex-36 491 1.56 QC- ACN- AA- XB 286

Ex-20 465.4 0.62 QC- ACN- TFA- XB 287

Ex-39 493 1.37 QC- ACN- AA- XB 288

Ex-2 477.3 1.17 QC- ACN- AA- XB 289

Ex-2 491.2 1.2 QC- ACN- AA- XB 290

Ex-2 477.3 1.08 QC- ACN- AA- XB 291

Ex-2 477.2 1.16 QC- ACN- AA- XB 292

Ex-2 477.4 1.14 QC- ACN- TFA- XB 293

Ex-2 477.4 1.19 QC- ACN- AA- XB 294

Ex-11 450.2 1.22 QC- ACN- TFA- XB 295

Ex-12 450.4 1.26 QC- ACN- AA- XB 296

Ex-2 449.5 0.67 QC- ACN- TFA- XB 297

Ex-2 449.2 1.21 QC- ACN- AA- XB 298

Ex-2 463.4 1.4 QC- ACN- AA- XB 299

Ex-2 449.2 1.21 QC- ACN- TFA- XB 300

Ex-2 489.1 1.42 QC- ACN- AA- XB 301

Ex-1 435.1 1.06 QC- ACN- TFA- XB 302

Ex-31 494.2 2.13 QC- ACN- AA- XB 303

Ex-2 464.3 1.68 QC- ACN- AA- XB 304

Ex-2 464 1.7 QC- ACN- AA- XB 305

Ex-2 450 1.51 QC- ACN- TFA- XB 306

Ex-2 475.4 1.27 QC- ACN- TFA- XB 307

Ex-31 524.4 0.74 QC- ACN- TFA- XB 308

Ex-31 559.3 1.74 QC- ACN- AA- XB

EXAMPLE 3093-chloro-5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one

-   General Method D: Tert-butyl    4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate    (25 mg, 0.050 mmol) was deprotected with 2:1 trifluoroacetic    acid/dichloromethane (1.2 mL, 0.050 mmol) for 45 min. Toluene (0.2    mL) was added to the reaction mixture and excess solvent was    evaporated. The resulting residue was stirred with isobutylene oxide    (0.023 mL, 0.251 mmol) and potassium carbonate (41.6 mg, 0.301 mmol)    in methanol (0.502 mL) at room temperature for 19 h. The reaction    mixture was partitioned between water and ethyl acetate (˜3.5 mL    total volume). The phases were separated, and the aqueous phase was    extracted with ethyl acetate (2×1 mL). The organic phases were    combined and excess solvent was evaporated off. DMF (1 mL) was added    to the resulting yellow residue, and the crude material was purified    via preparative LC/MS. Fractions containing the product were    combined and dried via centrifugal evaporation. The yield of    3-chloro-5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one    was 19.8 mg (82%), and its estimated purity by LCMS analysis was    98%. LCMS MH⁺: 470.3. HPLC Ret. Time 1.26 min. Method:    QC-ACN-TFA-XB. ¹H NMR: (500 MHz, DMSO-d₆) δ 10.77 (s, 1H), 7.71 (s,    1H), 7.47 (s, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H),    3.05 (d, J=11.2 Hz, 2H), 2.90 (dt, J=14.0, 7.0 Hz, 1H), 2.30-2.22    (m, 4H), 2.06 (s, 3H), 1.90 (s, 2H), 1.78-1.68 (m, 4H), 1.30 (d,    J=6.5 Hz, 6H), 1.11 (s, 6H).

The following examples were prepared in a manner similar to Example 309,using the indicated starting material.

TABLE 7 Ret Ex. Starting LCMS Time HPLC No. Structure Material MH⁺ (min)Method 310

Ex-2 436 1.45 QC- ACN- TFA- XB 311

Ex-11 437 1.18 QC- ACN- TFA- XB 312

Ex-12 437 1.28 QC- ACN- AA- XB 313

Ex-2 464 1.25 QC- ACN- AA- XB 314

Ex-2 464 1.42 QC- ACN- AA- XB 315

Ex-14 450.3 0.68 QC- ACN- TFA- XB 316

Ex-3 450.3 0.68 QC- ACN- TFA- XB 317

Ex-29 466.0 0.65 QC- ACN- TFA- XB 318

Ex-28 466.1 0.64 QC- ACN- TFA- XB 319

Ex-14 492.3 0.67 QC- ACN- TFA- XB 320

Ex-3 492.3 0.67 QC- ACN- TFA- XB 321

Ex-23 461.1 0.67 QC- ACN- TFA- XB 322

Ex-24 461.0 0.70 QC- ACN- TFA- XB 323

Ex-353 466 1.15 QC- ACN- AA- XB 324

Ex-2 450 1.38 QC- ACN- AA- XB 325

Ex-2 464.4 0.74 QC- ACN- AA- XB B1 326

Ex-54 500 1.11 QC- ACN- TFA- XB 327

Ex-31 489 1.41 QC- ACN- TFA- XB 328

Ex-36 478 1.57 QC- ACN- TFA- XB 329

Ex-46 512 1.72 QC- ACN- AA- XB

The following examples were prepared according to the general proceduresfor the above examples.

TABLE 8 Ret Ex. LCMS Time HPLC No. Structure MH⁺ (min) Method 330

554.2 1.4 QC- ACN- AA- XB 331

500 1.7 QC- ACN- AA- XB 332

484 1.3 QC- ACN- AA- XB 333

486 1.22 QC- ACN- TFA- XB 334

472 1.35 QC- ACN- TFA- XB 335

526 1.12 QC- ACN- TFA- XB 336

469 1.03 QC- ACN- TFA- XB 337

484 1.34 QC- ACN- AA- XB 338

510 1.5 QC- ACN- AA- XB 339

538 1.65 QC- ACN- AA- XB 340

498 1.55 QC- ACN- TFA- XB 341

488 1.45 QC- ACN- AA- XB 342

487 1.39 QC- ACN- AA- XB 343

501 1.45 QC- ACN- TFA- XB 344

483 1.08 QC- ACN- TFA- XB 345

478 1.35 QC- ACN- AA- XB 346

450 1.52 QC- ACN- AA- XB 347

436 1.2 QC- ACN- AA- XB 348

436 1.44 QC- ACN- AA- XB 349

499 1.09 QC- ACN- TFA- XB 350

488 1.42 QC- ACN- AA- XB 351

479.3 1.12 QC- ACN- TFA- XB 352

461.1 1.28 QC- ACN- TFA- XB

The following example was prepared according to the general proceduresof Examples 1 and 2 using the indicated fragment.

TABLE 9 Ret Ex. LCMS Time HPLC No. Structure Fragment MH⁺ (min) Method353

F-31A 394.2 0.62 A1

Biological Assays

The pharmacological properties of the compounds of this invention may beconfirmed by a number of biological assays. The exemplified biologicalassays, which follow, have been carried out with compounds of theinvention.

TLR7/8/9 Inhibition Reporter Assays

HEK-Blue™-cells (Invivogen) overexpressing human TLR7, TLR8 or TLR9receptors were used for screening inhibitors of these receptors using aninducible SEAP (secreted embryonic alkaline phosphatase) reporter geneunder the control of the IFN-β minimal promoter fused to five NF-κB andAP-1-binding sites. Briefly, cells are seeded into Greiner 384 wellplates (15000 cells per well for TLR7, 20,000 for TLR8 and 25,000 forTLR9) and then treated with test compounds in DMSO to yield a final doseresponse concentration range of 0.05 nM-50 μM. After a 30 minutecompound pre-treatment at room temperature, the cells are thenstimulated with a TLR7 ligand (gardiquimod at a final concentration of7.5 μM), TLR8 ligand (R848 at a final concentration of 15.9 μM) or TLR9ligand (ODN2006 at a final concentration of 5 nM) to activate NF-κB andAP-1 which induce the production of SEAP. After a 22 hour incubation at37° C., 5% CO₂, SEAP levels are determined with the addition ofHEK-Blue™ Detection reagent (Invivogen), a cell culture medium thatallows for detection of SEAP, according to manufacturer'sspecifications. The percent inhibition is determined as the % reductionin the HEK-Blue signal present in wells treated with agonist plus DMSOalone compared to wells treated with a known inhibitor.

TABLE 10 TLR7/8/9 Inhibition Data TLR7 TLR8 TLR9 Ex No. IC₅₀ (nM) IC₅₀(nM) IC₅₀ (nM) 1 27.5 15.4 621 2 1.6 5.1 4335 3 8.4 3.4 979 4 82.8 38.4756 5 178.7 107.0 763 6 12.8 13.3 580 8 72.7 43.5 957 9 50.8 11.5 879 10329.5 38.4 1540 11 5.3 3.3 4851 12 24.7 29.0 5225 13 18.2 33.9 593 143.5 3.6 1652 15 1.9 3.3 179 16 301.9 172.7 914 17 21.1 12.2 597 18 18.314.7 6653 19 25.7 39.7 792 20 6.0 17.0 1786 21 104.9 263.2 6540 22 1.110.7 2549 23 62.8 15.1 6265 24 75.9 10.7 3757 25 40.3 7.8 1372 26 12.08.9 1859 27 164.8 18.5 — 28 206.6 173.7 1206 29 14.1 50.9 783 30 8.410.1 2386 31 1.0 7.0 1121 32 1.8 17.2 1068 33 16.1 12.6 922 34 7.1 48.01463 35 60.0 6.8 574 36 9.6 81.2 1311 37 458.1 182.2 2432 38 51.2 30.33033 39 7.9 7.9 3181 40 5.2 16.9 4448 41 18.0 157.6 1120 42 40.9 134.16706 43 110.4 156.6 1562 44 3.8 19.4 2083 45 12.9 48.4 4667 46 2.9 29.9919 47 31.9 41.1 1885 48 13946.5 50000.0 1274 49 2614.0 2087.2 50000 506.8 7.7 411 51 10.9 30.6 2585 52 184.6 141.6 1521 53 11.4 10.3 — 54 23.45.9 753 55 13.9 202.8 2289 56 13.7 49.0 408 57 68.4 81.9 1357 58 5.4222.3 3480 59 46.6 270.4 5848 60 90.3 210.9 3062 61 2193.6 2275.1 208362 3125.0 3125.0 50000 63 3125.0 3125.0 50000 64 479.7 1082.2 7378 65975.5 75.1 3104 66 12.6 70.5 764 67 4.3 5.9 919 68 8.5 9.8 5359 69 333.1179.5 50000 70 8.6 26.1 2449 71 2.8 5.1 11002 72 21.8 17.3 50000 73 8.03.3 6074 74 20.9 4.9 4327 75 5.0 5.6 9325 76 4.4 4.7 19915 77 123.2 50.67851 78 67.6 64.0 34764 79 11.1 10.8 3794 80 127.6 140.7 48780 81 8.820.3 50000 82 9.5 11.9 799 83 3.9 1.2 7140 84 44.3 73.6 50000 85 2.2 4.68455 86 2.1 4.6 2543 87 3.1 5.7 2563 88 67.5 53.2 — 89 16.9 4.5 1958 9021.7 7.0 1973 91 2.6 5.0 4386 92 3.2 2.8 8512 93 5.0 4.9 5802 94 8.0 1.32033 95 7.0 7.8 6092 96 2.0 14.3 2861 97 5.2 9.7 2047 98 20.6 10.4 875299 7.1 10.3 4981 100 21.5 2.3 3055 101 12.8 9.3 4876 102 33.2 32.4 50000103 9.6 1.3 2083 104 13.1 3.5 2699 105 5.1 10.7 5517 106 6.2 5.5 1248107 6.6 4.4 13353 108 32.8 2.0 7542 109 13.0 9.7 5306 110 56.1 163.55258 111 48.0 157.5 3060 112 38.9 70.5 2363 113 26.4 70.7 2189 114 42.943.6 10375 115 48.0 42.1 6594 116 29.6 23.8 6099 117 2.0 5.3 13975 11818.6 14.5 9636 119 11.4 14.9 1155 120 7.4 11.5 851 121 40.7 102.3 50000122 4.9 15.7 14719 123 7.0 8.0 23803 124 9.7 11.3 50000 125 3125.0 288.750000 126 3125.0 631.4 50000 127 3.7 5.2 33623 128 3.0 5.7 977 129 5.08.0 2928 130 289.6 25.9 8506 131 244.6 33.4 16237 132 9.0 15.1 25521 13324.1 6.2 14874 134 11.9 8.7 3461 135 5.3 5.6 18958 136 12.0 13.6 1954137 19.9 12.3 11508 138 17.5 5.2 7613 139 15.4 4.2 10356 140 47.8 39.721905 141 27.9 37.3 4457 142 204.9 95.4 7649 143 413.2 99.7 2717 14459.9 4.7 11388 145 63.8 10.7 7175 146 38.8 4.5 6992 147 56.3 4.8 5016148 193.4 364.0 50000 149 16.0 27.3 23168 150 1.2 4.4 11377 151 1.2 13.711046 152 1.4 4.6 16580 153 3.5 12.6 7883 154 4.6 26.6 13839 155 5.324.2 21139 156 4.3 7.4 11792 157 12.8 12.2 6387 158 6.6 2.6 3525 15910.2 19.7 16617 160 8.9 14.5 14739 161 50.5 239.5 8734 162 8.4 99.4 4120163 12.3 117.6 3887 164 7.0 42.4 2555 165 45.8 113.4 10083 167 61.7 15.649253 168 7.9 10.3 2380 169 11.9 6.2 1800 170 19.8 14.4 2075 171 5.110.4 25229 172 29.9 6.9 151 173 3125.0 983.1 6611 174 15.7 44.8 50000175 275.1 87.5 15517 176 1.3 1.3 177 177 154.5 51.9 9211 178 3.9 3.27087 179 95.1 28.8 3928 180 7.0 8.2 5745 181 2.0 8.5 13516 182 5.9 7.35547 183 28.5 31.4 9652 184 71.8 34.2 2124 185 61.3 19.0 4325 186 112.275.5 6730 187 85.4 30.1 655 188 14.1 11.1 526 189 25.5 25.0 47836 19025.6 53.8 2265 191 6.9 21.5 8842 192 6.4 12.0 2824 193 12.6 11.7 8916194 10.2 6.3 2979 195 3.9 2.6 5191 196 3.0 2.4 4978 197 4.6 2.4 8342 1989.1 13.4 50000 199 1.9 4.2 1550 200 4.3 2.2 3739 201 4.0 4.4 959 20211.3 13.5 5634 203 271.7 28.7 16865 204 14.6 18.0 50000 205 500.8 19.88709 206 18.9 2.6 4495 207 20.8 11.7 46799 208 31.1 7.0 3109 209 34.318.0 17495 210 24.7 2.7 5031 211 34.6 17.1 50000 212 17.1 17.4 12619 21315.6 16.5 2906 214 13.9 7.9 5692 215 66.1 54.9 17176 217 659.5 162.810935 219 48.0 9.1 22305 220 24.5 1.4 2785 221 67.0 9.3 25379 222 15.60.9 3067 223 10.0 13.6 5907 224 1.8 4.5 14025 225 4.6 3.6 6989 226 3.87.0 10444 227 3.8 4.1 3037 228 3.6 4.3 4269 229 5.7 4.2 50000 230 11.223.1 5513 231 7.0 22.3 3227 232 2.9 1.1 6010 233 57.7 97.0 — 234 40.252.3 — 235 11.0 5.2 1767 236 4.6 9.8 980 237 181.1 19.8 2104 238 7.211.8 8334 239 5.4 5.3 5808 240 1.0 3.7 2588 241 8.3 4.8 4866 242 3.2 5.12680 243 1.4 9.1 1772 244 6.0 1.8 954 245 7.3 2.0 851 246 2.9 1.7 387247 3.0 4.1 864 248 5.6 16.9 30048 249 14.1 1.1 1765 250 6.3 4.8 3006251 3.5 8.1 3527 252 4.2 2.7 2657 253 6.1 5.2 1241 254 5.5 2.1 2666 2554.8 2.3 1819 256 12.4 1.7 1473 257 15.6 1.1 1979 258 4.5 1.1 832 259 6.10.6 983 260 23.2 3.1 2237 261 8.8 7.1 3361 262 47.7 52.3 2121 263 10.824.1 1565 264 13.5 927.2 6088 265 20.1 42.6 5026 266 11.6 15.8 4481 2672.2 6.6 3535 268 2.4 6.6 2626 269 35.5 4.6 5904 270 2.1 4.7 4159 271 5.38.3 13527 272 7.9 53.0 — 273 90.2 16.0 2078 274 183.3 15.3 1589 275193.8 95.7 3194 276 52.2 80.2 4764 277 9.3 21.0 15626 278 5.3 21.0 3202279 23.1 5.9 7059 280 6.1 9.0 4569 281 47.4 29.6 5697 282 5.2 7.0 6273283 512.1 46.8 6246 284 6.5 21.8 1655 285 14.6 99.1 3414 286 5.0 5.6 289287 7.8 8.6 18171 288 17.4 61.7 2498 289 5.9 12.3 5283 290 8.3 17.1 1085291 12.3 11.2 1417 292 7.2 40.7 492 293 21.6 74.9 12500 294 12.5 16.93316 295 114.2 61.9 9687 296 1.1 3.0 4308 297 4.4 5.5 3994 298 168.6147.7 21284 299 3.7 4.3 504 300 42.6 42.5 50000 301 25.7 36.5 1830 30220.4 213.8 50000 303 9.6 49.9 50000 304 7.8 80.0 50000 305 11.0 97.550000 306 16.5 26.9 547 307 7.5 11.2 2748 308 2.0 22.1 5655 309 13.7 5.38509 310 2.3 1.3 5543 311 17.7 3.9 3145 312 35.1 22.2 3171 313 4.7 3.18036 314 5.2 5.1 10069 315 6.7 1.8 4938 316 10.2 1.9 3086 317 19.3 7.23585 318 360.6 22.3 3433 319 10.9 1.6 4328 320 14.2 1.7 2310 321 36.71.6 4370 322 45.7 1.0 4789 323 18.4 13.9 7177 324 2.5 2.8 11550 325 8.74.3 3002 326 6.1 0.6 1661 327 6.0 1.6 3279 328 49.1 54.7 5969 329 15.832.4 — 330 7.7 432.2 705 331 6.3 9.6 2713 332 4.9 1.1 789 333 92.2 11.13009 334 8.6 0.8 487 335 2.4 5.9 529 336 10.2 1.2 553 337 1.8 11.9 2492338 1.1 13.5 772 339 28.9 2143.7 1023 340 4.5 16.6 1210 341 16.2 4.3 714342 12.9 16.0 3333 343 18.3 14.2 1168 344 11.5 26.5 322 345 11.1 16.97048 346 37.9 86.8 16676 347 7.2 28.6 13597 348 7.1 25.3 10830 349 14.572.6 782 350 14.4 1.4 2139 351 78.5 134.6 11923 352 21.5 31.5 2416

What is claimed is:
 1. A compound of Formula (I)

or a salt thereof, wherein: Y is

R₁ is H, Cl, —CN, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃hydroxy-fluoroalkyl, —CR_(z)═CH₂, C₃₋₆ cycloalkyl, —CH₂(C₃₋₆cycloalkyl), —C(O)O(C₁₋₃ alkyl), or tetrahydropyranyl; R₂ is C₁₋₆ alkyl,C₁₋₃ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃ aminoalkyl, —(CH₂)₀₋₄O(C₁₋₃alkyl), C₃₋₆ cycloalkyl, —(CH₂)₁₋₃C(O)NR_(x)R_(x), —CH₂(C₃₋₆cycloalkyl), —CH₂(phenyl), tetrahydrofuranyl, tetrahydropyranyl, orphenyl; each R_(2a) is independently H, halo, —CN, —NR_(x)R_(x), C₁₋₆alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ fluoroalkoxy,—(CH₂)₀₋₂O(C₁₋₃ alkyl), —(CH₂)₀₋₃C(O)NR_(x)R_(x), —(CH₂)₁₋₃(C₃₋₆cycloalkyl), —C(O)O(C₁₋₃ alkyl), —C(O)NR_(x)(C₁₋₃ alkyl),—CR_(x)═CR_(x)R_(x), —CR_(x)═CH(C₃₋₆ cycloalkyl), —C(O)(pyrrolidinyl),or a cyclic group selected from pyrrolidinyl, pyrazolyl, phenyl,pyridinyl, and pyrimidinyl, each substituted with zero, 1, or 2 R_(y);each R_(y) is independently F, Cl, —CN, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl,C₁₋₃ alkoxy, —NR_(x)C(O)(C₁₋₃ alkyl), —C(O)NR_(x)R_(x), C₃₋₆ cycloalkyl,piperidinyl, or morpholinyl; R_(2b) is R₂ or R_(2a); R_(2c) is R₂ orR_(2a); provided that one of R_(2b) and R_(2c) is R₂, and the other ofR_(2b) and R_(2c) is R_(2a); R₃ is (a) -L₁-A; or (b) H, C₁₋₆ alkyl, C₁₋₆fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃ cyanoalkyl, —(CH₂)₀₋₄O(C₁₋₃ alkyl),—(CH₂CH₂O)₂₋₃O(C₁₋₃ alkyl), —CH₂CH₂NR_(x)R_(x), —CR_(x)R_(x)C(O)OH,—(CR_(x)R_(x))₀₋₂C(O)NR_(x)R_(x), —CH₂C(O)NR_(x)(C₁₋₃ alkyl),—CH₂C(O)NR_(x)(C₁₋₄ hydroxyalkyl), —(CR_(x)R_(x))₀₋₂S(O)₂(C₁₋₃ alkyl),—C(O)(C₁₋₃ alkyl), —C(O)(C₁₋₃ fluoroalkyl), —C(O)CR_(x)R_(x)NR_(x)R_(x),—C(O)(C₁₋₆ hydroxyalkyl), or —NR_(x)C(O)(C₁₋₃ alkyl); L₁ is a bond,—(CR_(x)R_(x))₁₋₂—, —(CR_(x)R_(x))₁₋₂CR_(x)(OH)—, —(CR_(x)R_(x))₁₋₂O—,—CR_(x)R_(x)C(O)—, —(CR_(x)R_(x))₂NR_(x)(CR_(x)R_(x))₀₋₁—,—CR_(x)R_(x)C(O)NR_(x)(CR_(x)R_(x))₀₋₄—, —C(O)(CR_(x)R_(x))₀₋₃—,—C(O)(CR_(x)R_(x))₀₋₂NR_(x)(CR_(x)R_(x))₀₋₂—,—C(O)(CR_(x)R_(x))₀₋₂NR_(x)(CR_(x)R_(x))₁₋₂CR_(x)(OH)—,—C(O)(CR_(x)R_(x))₁₋₂C(O)NR_(x)—,—(CR_(x)R_(x))₀₋₂C(O)NR_(x)(CR_(x)R_(x))₁₋₂CR_(x)(OH)—,—C(O)(CR_(x)R_(x))₀₋₁O—, —C(O)(CR_(x)R_(x))₁₋₂NHS(O)₂—,—C(O)NR_(x)(CR_(x)R_(x))₁₋₂—, or —S(O)₂(CR_(x)R_(x))₀₋₂—; A isadamantanyl, azepanyl, azetidinyl, C₃₋₆ cycloalkyl, diazepanyl,dihydroinonyl, dihydropyrimidinonyl, dioxidoisothiazolidinyl,dioxidothiazinanyl, dioxotetrahydrothiophenyl,dioxotetrahydrothiopyranyl, dioxothiomorpholinyl, furanyl, imidazolyl,imidazolidinonyl, indolyl, isoquinolinyl, isoxazolyl, morpholinyl,morpholinonyl, naphthalenyl, oxazolidinonyl, oxadiazolyl, oxetanyl,oxazolyl, phenyl, piperidinyl, piperidinonyl, piperazinyl,piperazinonyl, pyrazinyl, pyrazolyl, pyrazolidinonyl, pyridazinonyl,pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidin-dionyl,pyrrolidinyl, pyrrolyl, quinolinyl, quinolizinonyl, tetrahydrofuranyl,tetrahydrofuranonyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl,thiazolyl, or triazolyl, each substituted with zero, 1, or 2 R_(3a);each R_(3a) is independently F, Cl, —OH, —NH₂, C₁₋₃ alkyl, C₁₋₂fluoroalkyl, or —C(O)NR_(x)R_(x); each R₄ is independently F, —OH, C₁₋₂alkyl, or —OCH₃; or two R₄ attached to the same carbon atom form ═O;each R₅ is independently F, Cl, —CN, C₁₋₂ alkyl, C₁₋₂ fluoroalkyl, or—OCH₃; each R_(x) is independently H or —CH₃; R_(z) is H, C₁₋₂ alkyl, orC₁₋₂ fluoroalkyl; m is zero, 1, 2, 3, or 4; and n is zero, 1, 2, or 3.2. The compound according to claim 1 or a salt thereof, wherein: R₁ isH, C₁₋₄ alkyl, C₁₋₃ fluoroalkyl, or C₃₋₆ cycloalkyl; R₂ is C₁₋₄ alkyl,C₁₋₂ fluoroalkyl, C₁₋₄ hydroxyalkyl, —(CH₂)₁₋₃OCH₃, C₃₋₆ cycloalkyl,—CH₂C(O)NR_(x)R_(x), —CH₂(C₃₋₆ cycloalkyl), —CH₂(phenyl),tetrahydrofuranyl, or phenyl; each R_(2a) is independently H, F, Cl,—CN, —NR_(x)R_(x), C₁₋₆ alkyl, C₁₋₂ fluoroalkyl, C₁₋₃ hydroxyalkyl,—(CH₂)₀₋₂O(C₁₋₂ alkyl), —(CH₂)₀₋₂C(O)NR_(x)R_(x),—(CH₂)₁₋₃(cyclopropyl), —C(O)O(C₁₋₂ alkyl), —C(O)NR_(x)(C₁₋₃ alkyl),—CR_(x)═CH₂, —CH═CH(C₃₋₆ cycloalkyl), —C(O)(pyrrolidinyl), or a cyclicgroup selected from pyrrolidinyl, pyrazolyl, phenyl, pyridinyl, andpyrimidinyl, each substituted with zero, 1, or 2 R_(y); each R_(y) isindependently F, Cl, —CN, C₁₋₂ alkyl, C₁₋₂ alkoxy, —NR_(x)C(O)(C₁₋₂alkyl), —C(O)NR_(x)R_(x), C₃₋₆ cycloalkyl, or morpholinyl; R₃ is (a)-L₁-A; or (b) H, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₃cyanoalkyl, —(CH₂)₀₋₃O(C₁₋₂ alkyl), —(CH₂CH₂O)₂₋₃O(C₁₋₂ alkyl),—CH₂CH₂NR_(x)R_(x), —CR_(x)R_(x)C(O)OH,—(CR_(x)R_(x))₀₋₂C(O)NR_(x)R_(x), —CH₂C(O)NR_(x)(C₁₋₂ alkyl),—CH₂C(O)NH(C₁₋₄ hydroxyalkyl), —(CR_(x)R_(x))₁₋₂S(O)₂(C₁₋₂ alkyl),—C(O)(C₁₋₂ alkyl), —C(O)(C₁₋₂ fluoroalkyl), —C(O)CR_(x)R_(x)NR_(x)R_(x),—C(O)(C₁₋₄ hydroxyalkyl), or —NR_(x)C(O)(C₁₋₂ alkyl); L₁ is a bond,—(CR_(x)R_(x))₁₋₂—, —CR_(x)R_(x)C(O)—, —C(O)(CR_(x)R_(x))₀₋₁—, —C(O)O—,or —S(O)₂(CR_(x)R_(x))₀₋₂—; A is azetidinyl, C₃₋₆ cycloalkyl,dioxotetrahydrothiophenyl, oxetanyl, phenyl, piperidinyl, pyrazolyl,pyrazolidinonyl, pyrrolidinonyl, pyrrolidin-dionyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrofuranonyl, tetrahydropyranyl, or triazolyl,each substituted with zero, 1, or 2 R_(3a); each R_(3a) is independentlyF, Cl, —OH, —NH₂, C₁₋₃ alkyl, C₁₋₂ fluoroalkyl, or —C(O)NR_(x)R_(x);each R₄ is independently F, —OH, —CH₃, or —OCH₃; or two R₄ attached tothe same carbon atom form ═O; each R₅ is independently F, —CN, —CH₃,—CF₃, or —OCH₃; and R_(z) is H or —CH₃.
 3. The compound according toclaim 1 or a salt thereof, wherein: R₁ is —CH₂CH₃ or —CH(CH₃)₂; R₂ is—CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH₂C(CH₃)₂OH, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂OCH₃, —CH₂(cyclopropyl),—CH₂(phenyl), —CH₂C(O)NH₂, tetrahydrofuranyl, or phenyl; each R_(2a) isindependently H, F, Cl, —CN, —NH₂, C₁₋₅ alkyl, —CF₃, —CH₂OH, —OCH₃,—CH₂OCH₃, —CH₂CH₂(cyclopropyl), —C(O)OCH₃, —C(O)N(CH₃)₂,—C(O)NH(CH₂CH₂CH₃), —CH═CH₂, —C(CH₃)═CH₂, —CH═CH(cyclopropyl),—C(O)(pyrrolidinyl), or a cyclic group selected from pyrrolidinyl,pyrazolyl, phenyl, pyridinyl, and pyrimidinyl, each substituted withzero, 1, or 2 R_(y); each R_(y) is independently F, —CN, —CH₃, —CF₃,—OCH₃, —NHC(O)CH₃, —C(O)NH₂, —C(O)NH(CH₃), cyclopropyl, or morpholinyl;R_(2b) is R₂ or R_(2a); R_(2c) is R₂ or R_(2a); provided that one ofR_(2b) and R_(2c) is R₂, and the other of R_(2b) and R_(2c) is R_(2a);R₃ is H, —CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂,—CH₂CH₂CH(CH₃)₂, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH(CF₃)₂, —CH₂CH₂OH,—CH₂CH₂CH₂OH, —C(CH₃)₂OH, —CH₂C(CH₃)₂OH, —CH₂CH₂C(CH₃)₂OH,—CH₂CH(OH)CH(CH₃)₂, —CH₂CH(OH)CH₂OH, —CH(CH₂CH₂OH)₂, —CH₂CN, —CH₂CH₂CN,—CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃, —(CH₂CH₂O)₂₋₃OCH₃, —CH₂CH₂NH(CH₃),—C(CH₃)₂C(O)OH, —CH₂C(O)NH₂, —CH₂C(O)NH(CH₃), —CH₂C(O)N(CH₃)₂,—CH₂C(O)NH(CH₂CH₃), —CH₂C(O)NH(CH₂CH(CH₃)OH), —CH₂C(O)NH(CH₂C(CH₃)₂OH),—CH(CH₃)C(O)NH₂, —C(CH₃)₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂CH₂S(O)₂CH₃,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂N(CH₃)₂, —C(O)C(CH₃)₂NH₂,—C(O)CH(CH₃)NH(CH₃), —C(O)C(CH₃)₂NH(CH₃), —C(O)CH₂CH(CH₃)OH,—C(O)CH₂C(CH₃)₂OH, —C(O)C(CH₃)₂CH₂OH, —NHC(O)CH₃, —CH₂(methyltriazolyl), —CH₂(trifluoromethyl phenyl), —CH₂(difluoromethyl,fluorophenyl), —CH₂(fluoro, chlorophenyl), —CH₂(difluorocyclopropyl),—CH₂CH₂(pyrrolidin-dionyl), —CH₂(oxetanyl), —CH₂(tetrahydropyranyl),—CH₂C(O)(hydroxypyrrolidinyl), —CH₂C(O)(pyrazolidinonyl),—CH₂C(O)(pyrrolidinyl), —CH₂(dimethyl pyrazolyl), —CH₂(methylpyrazolyl), —CH₂(pyrazolyl), —CH₂(cyclopropyl), —CH₂(tetrahydrofuranyl),—CH₂(i-propyl pyrazolyl), —CH₂(n-propyl pyrazolyl), —CH(CH₃)(methylpyrazolyl), —C(O)(aminocyclopropyl), —C(O)(hydroxypyrrolidinyl),—C(O)(methyl, hydroxypyrrolidinyl), —C(O)CH₂(pyrrolidinonyl),—C(O)CH₂(pyrrolidinyl), —C(O)O(methyl pyrrolidinyl),—S(O)₂CH₂CH₂(pyrrolidinyl), —CH₂(hydroxytetrahydropyranyl), or a cyclicgroup selected from cyclopentyl, cyclohexyl, oxetanyl, azetidinyl,pyrrolidinonyl, tetrahydrofuranyl, tetrahydrofuranonyl,tetrahydropyranyl, piperidinyl, and dioxotetrahydrothiophenyl, eachsubstituted with zero, 1, or 2 R_(3a); each R_(3a) is independently F,—OH, —CH₃, —CH(CH₃)₂, —CF₃, or —C(O)NH₂; R₅ is F; m is zero; and n iszero or
 1. 4. The compound according to claim 1 or a salt thereof,wherein Y is


5. The compound according to claim 1 or a salt thereof, wherein Y is


6. (canceled)
 7. (canceled)
 8. A pharmaceutical composition comprising acompound according to claim 1 or a pharmaceutically-acceptable saltthereof; and a pharmaceutically acceptable carrier.
 9. (canceled) 10.(canceled)
 11. (canceled)
 12. The compound according to claim 1 or asalt thereof, wherein: R₃ is -L₁-A.
 13. The compound according to claim1 or a salt thereof, wherein: R₃ is -L₁-A; and L₁ is a bond.
 14. Thecompound according to claim 1 or a salt thereof, wherein: R₃ is -L₁-A;and L₁ is —(CR_(x)R_(x))₁₋₂—, —CR_(x)R_(x)C(O)—, —C(O)(CR_(x)R_(x))₀₋₁—,—C(O)O—, or —S(O)₂(CR_(x)R_(x))₀₋₂—.
 15. The compound according to claim1 or a salt thereof, wherein: R₃ is H, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl,C₁₋₆ hydroxyalkyl, C₁₋₃ cyanoalkyl, —(CH₂)₀₋₃O(C₁₋₂ alkyl),—(CH₂CH₂O)₂₋₃O(C₁₋₂ alkyl), —CH₂CH₂NR_(x)R_(x), —CR_(x)R_(x)C(O)OH,—(CR_(x)R_(x))₀₋₂C(O)NR_(x)R_(x), —CH₂C(O)NR_(x)(C₁₋₂ alkyl),—CH₂C(O)NH(C₁₋₄ hydroxyalkyl), —(CR_(x)R_(x))₁₋₂S(O)₂(C₁₋₂ alkyl),—C(O)(C₁₋₂ alkyl), —C(O)(C₁₋₂ fluoroalkyl), —C(O)CR_(x)R_(x)NR_(x)R_(x),—C(O)(C₁₋₄ hydroxyalkyl), or —NR_(x)C(O)(C₁₋₂ alkyl).
 16. The compoundaccording to claim 1 or a salt thereof, wherein said compound isselected from:5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-on(1);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(2);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(3);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,6-dimethylpyridin-2(1H)-one(6);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(8);3-amino-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(9);3-fluoro-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(13);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(14);1-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(15);1-isopropyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)pyridin-2(1H)-one(16);3-amino-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(19);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1-methylpyridin-2(1H)-one(20);3-chloro-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(22);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(23);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(24);3-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,6-dimethylpyridin-2(1H)-one(25);1-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3,4-dimethylpyridin-2(1H)-one(26);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1,6-dimethylpyridin-2(1H)-one(28);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1,4-dimethylpyridin-2(1H)-one(29);1-(2-hydroxyethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(30);3-chloro-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(31);3-chloro-1-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)pyridin-2(1H)-one(32);3-chloro-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,6-dimethylpyridin-2(1H)-one(33);1-(cyclopropylmethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(34);1,3-diethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-6-methylpyridin-2(1H)-one(35);1-isobutyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(36); methyl5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate(37);1-(3-hydroxypropyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(38);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-(2-methoxyethyl)-3-methylpyridin-2(1H)-one(39);1-(2,2-difluoroethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(40);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(trifluoromethyl)pyridin-2(1H)-one(41);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methyl-1-(tetrahydrofuran-3-yl)pyridin-2(1H)-one (42);1-(2-hydroxy-2-methylpropyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(43);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methyl-1-phenylpyridin-2(1H)-one(44);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methyl-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one(45);1-benzyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(46);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(47);1-(2-hydroxy-2-methylpropyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)pyridin-2(1H)-one(48);2-(5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2-oxopyridin-1(2H)-yl)acetamide(49);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(50);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(prop-1-en-2-yl)pyridin-2(1H)-one(51);(E)-3-(2-cyclopropylvinyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(52);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-phenylpyridin-2(1H)-one(53);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(54);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(p-tolyl)pyridin-2(1H)-one(55);3-(5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzonitrile(56);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2′-methoxy-1-methyl-[3,3′-bipyridin]-2(1H)-one(57);3-(5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzamide(58);3-(5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N-methylbenzamide(59);N-(3-(5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)acetamide(60);3-(3,3-dimethylbutyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(61);3-(2-cyclopropylethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(62);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-N,N,1-trimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide(63);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-2-oxo-N-propyl-1,2-dihydropyridine-3-carboxamide(64);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-[3,3′-bipyridin]-2(1H)-one(65);3-isopropyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(66);3-ethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(67);1,3-diethyl-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)pyridin-2(1H)-one(68);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrrolidine-1-carbonyl)pyridin-2(1H)-one (69);3-(hydroxymethyl)-5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(70);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(71);5-(3-isopropyl-5-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(72);5-(5-(1-(3-hydroxy-3-methylbutyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(73);5-(5-(1-(3-hydroxy-3-methylbutyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(74);5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(75);3-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)propanenitrile(76); 5-(3-isopropyl-5-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(77);5-(5-(1-(5-(difluoromethoxy)-2-fluorobenzyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(78);5-(3-isopropyl-5-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(79);5-(5-(1-(5-chloro-2-fluorobenzyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(80);5-(5-(1-(1,1-dioxidotetrahydrothiophen-3-yl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(81);3-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)propanamide (82);5-(5-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(83);1-(2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)ethyl)pyrrolidine-2,5-dione(84);5-(5-(1-(3-hydroxypropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(85);5-(5-(1-isopentylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(86);5-(5-(1-cyclohexylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(87);5-(3-isopropyl-5-(1-(4,4,4-trifluoro-3-(trifluoromethyl)butyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(88);5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-3-phenylpyridin-2(1H)-one(89);5-(5-(1-isopentylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-3-phenylpyridin-2(1H)-one(90);3-chloro-5-(5-(1-isopentylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(91);3-chloro-5-(3-isopropyl-5-(1-(oxetan-3-ylmethyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(92);3-chloro-5-(3-isopropyl-5-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(93);5-(3-isopropyl-5-(1-(oxetan-3-ylmethyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(94);3-chloro-5-(3-isopropyl-5-(1-(2-methoxyethyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(95);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetonitrile(96);3-chloro-5-(5-(1-cyclopentylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(97); 3-chloro-5-(3-isopropyl-5-(1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one (98);3-chloro-5-(3-isopropyl-5-(1-(3-methoxypropyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(99);5-(3-isopropyl-5-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(100);3-chloro-5-(3-isopropyl-5-(1-(2-(2-methoxyethoxy)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(101); 3-chloro-5-(3-isopropyl-5-(1-(3,3,3-trifluoropropyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one (102);5-(3-isopropyl-5-(1-(2-methoxyethyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(103);5-(3-isopropyl-5-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(104);3-chloro-5-(3-isopropyl-5-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(105);3-chloro-5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(106); 3-chloro-5-(3-isopropyl-5-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one (107);5-(3-isopropyl-5-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one (108);5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-(2-methoxyethyl)-3-methylpyridin-2(1H)-one(109);1-isobutyl-5-(3-isopropyl-5-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(110);1-benzyl-5-(3-isopropyl-5-(1-(4,4,4-trifluorobutyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(111);1-isobutyl-5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(112);1-benzyl-5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(113);2-(4-(3-isopropyl-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(114);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(117);(S)-5-(5-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(119); (R)-5-(5-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(120);5-(3-isopropyl-5-(1-(2-oxo-2-(3-oxopyrazolidin-1-yl)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(121); 5-(3-isopropyl-5-(1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one (122);(R)-5-(3-isopropyl-5-(1-(2-oxopyrrolidin-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3 -dimethylpyridin-2(1H)-one (123);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-(2-hydroxy-2-methylpropyl)acetamide (124);(R)-2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-(2-hydroxypropyl)acetamide (125);(S)-2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-(2-hydroxypropyl)acetamide (126);5-(3-isopropyl-5-(1-(1-methyl-2-oxopyrrolidin-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(127);2-(4-(3-isopropyl-2-(5-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (128);2-(4-(3-isopropyl-2-(5-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide (129);2-(4-(2-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide (132);2-(4-(2-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (133);2-(4-(3-isopropyl-2-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (134);2-(4-(3-isopropyl-2-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide (135);2-(4-(2-(1-ethyl-4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (136);2-(4-(2-(1-ethyl-4,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide (137);2-(4-(3-isopropyl-2-(1,2,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(138);2-(4-(3-isopropyl-2-(1,2,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide (139);2-(4-(3-isopropyl-2-(5-methoxy-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(140);2-(4-(3-isopropyl-2-(5-methoxy-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(141);2-(4-(3-isopropyl-2-(5-methoxy-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(142);2-(4-(3-isopropyl-2-(5-methoxy-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(143);2-(4-(2-(5-cyano-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(144);2-(4-(2-(5-cyano-1,2-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(145);2-(4-(2-(5-cyano-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(146);2-(4-(2-(5-cyano-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(147);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-2-methylpropanoic acid (148);5-(3-isopropyl-5-(1-(5-methyl-2-oxotetrahydrofuran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(149);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (150);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-2-methylpropanamide(151);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(152);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(153);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-2-methylpropanamide(154);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-ethylacetamide(155);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)propanamide(156);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-ethyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (157);2-(4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluoro-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(158);2-(4-(3-isopropyl-2-(1-(2-methoxyethyl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(159);2-(4-(3-isopropyl-2-(1-(2-methoxyethyl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide(160);2-(4-(2-(1-isobutyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide (161);2-(4-(2-(1-benzyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide (162);2-(4-(2-(1-isobutyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (163);2-(4-(2-(1-benzyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (164);2-(4-(3-isopropyl-2-(5-methyl-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(165);2-(4-(2-(1-(2,2-difluoroethyl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(166);2-(4-(2-(1-(2-hydroxyethyl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(167);2-(4-(2-(5-ethyl-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(168);2-(4-(3-isopropyl-2-(1-methyl-2-oxo-1,2-dihydro-[3,3′-bipyridin]-5-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(169);2-(4-(3-isopropyl-2-(1-methyl-6-oxo-5-phenyl-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(170);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(171);5-(3-isopropyl-5-(1-(2-(methylamino)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(172);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(piperidin-1-yl)pyridin-2(1H)-one (173);5-(5-(1-(1-acetylazetidin-3-yl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-chloro-1,4-dimethylpyridin-2(1H)-one(174);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(175);5-(3-isopropyl-5-(1-(2-(methylamino)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(176);5-(3-isopropyl-5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(177); 5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one (178);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(179);5-(3-isopropyl-5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(180);5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(181);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(182);5-(3-isopropyl-5-(1-((1-methyl-1H-pyrazol-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(195);5-(3-isopropyl-5-(1-((1-methyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(196); 5-(3-isopropyl-5-(1-((1-methyl-1H-pyrazol-5-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(197);5-(3-isopropyl-5-(1-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(198);5-(5-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(199);5-(5-(1-((4H-pyrazol-3-yl)methyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(200);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1-methylpyridin-2(1H)-one(201);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1-methylpyridin-2(1H)-one(202);1-ethyl-5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(204);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(206);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(207);1-ethyl-5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3,4-dimethylpyridin-2(1H)-one(208);1-ethyl-5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-3,4-dimethylpyridin-2(1H)-one(209); 5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one (210);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(211);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(212);1-ethyl-5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-3,4-dimethylpyridin-2(1H)-one(213);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(214); 5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1,4-dimethylpyridin-2(1H)-one(215);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1,4-dimethylpyridin-2(1H)-one(216);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1,6-dimethylpyridin-2(1H)-one(217);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methoxy-1,6-dimethylpyridin-2(1H)-one(218);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(219);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(220);5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(221);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(222);5-(5-(1-(cyclopropylmethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(223);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(224);5-(3-isopropyl-5-(1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(225);3-chloro-5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(226);3-chloro-5-(3-isopropyl-5-(1-((1-isopropyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(227); 5-(3-isopropyl-5-(1-((1-propyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one (228);N-(4-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)cyclohexyl)acetamide (229);5-(3-isopropyl-5-(1-(4-(trifluoromethyl)cyclohexyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one (230);5-(3-isopropyl-5-(1-(4-(trifluoromethyl)cyclohexyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(231);5-(5-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(232);5-(3-isopropyl-5-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(233);5-(3-isopropyl-5-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(234);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(235);5-(5-(1-(2-hydroxyethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(236);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-[3,3′-bipyridin]-2(1H)-one(237);3-chloro-5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(238);3-chloro-5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(241);3-chloro-5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(240);5-(5-(1-acetylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-chloro-1,4-dimethylpyridin-2(1H)-one(241);3-chloro-5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(242);3-chloro-5-(5-(1-(1,5-dihydroxypentan-3-yl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(243);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(244);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(245);5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one (246);5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(247);3-chloro-5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(248);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(249);3-chloro-5-(3-isopropyl-5-(1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(250);5-(5-(1-butylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-chloro-1,4-dimethylpyridin-2(1H)-one(251);3-chloro-5-(3-isopropyl-5-(1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(252);3-chloro-5-(5-(1-(2,3-dihydroxypropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(253);3-chloro-5-(3-isopropyl-5-(1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(254-255);5-(5-(1-isobutylpiperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(256);5-(3-isopropyl-5-(1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(257);5-(4-fluoro-3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(258);5-(4-fluoro-3-isopropyl-5-(1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(259);1-ethyl-5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-3-(pyrimidin-5-yl)pyridin-2(1H)-one(260);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1-(2-methoxyethyl)-3-methylpyridin-2(1H)-one(261);1-isobutyl-5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(262);1-benzyl-5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(263);1-(2-hydroxyethyl)-5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(264);5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-3-methyl-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one(265);1-(2,2-difluoroethyl)-5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(266);5-(5-(1-(4-(2-hydroxypropan-2-yl)cyclohexyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(267-268);5-(3-isopropyl-5-(1-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(269);5-(5-(1-(4-(2-hydroxypropan-2-yl)cyclohexyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(270);5-(5-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(271);5-(5-(1-(1-aminocyclopropanecarbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(272);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(273);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(274);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methoxy-1,6-dimethylpyridin-2(1H)-one(275);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methoxy-1,4-dimethylpyridin-2(1H)-one(276);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(277);3-chloro-5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(278);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(279);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(280); 5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-ethyl-3,4-dimethylpyridin-2(1H)-one(281);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-ethyl-3-methylpyridin-2(1H)-one(282);1-benzyl-5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(284); 5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-isobutyl-3-methylpyridin-2(1H)-one(285);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methoxy-1-methylpyridin-2(1H)-one(286);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-(2-methoxyethyl)-3-methylpyridin-2(1H)-one(287);5-(5-(1-((2R,4S)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(288);5-(5-(1-((2S,4R)-4-hydroxy-1-methylpyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(289);5-(5-(1-((2S,4R)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(290);5-(5-(1-((2S,3S)-3-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(291);5-(5-(1-((2R,4S)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(292);5-(5-(1-((2S,4R)-4-hydroxypyrrolidine-2-carbonyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(293);5-(5-(1-(2-amino-2-methylpropanoyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(296);5-(3-isopropyl-5-(1-(methyl-L-alanyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(297);5-(3-isopropyl-5-(1-(2-methyl-2-(methylamino)propanoyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(298);5-(3-isopropyl-5-(1-(methyl-D-alanyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(299);5-(3-isopropyl-5-(1-(2-(2-oxopyrrolidin-1-yl)acetyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(300);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(301); 3-chloro-5-(3-isopropyl-5-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one (302);5-(5-(1-(3-hydroxy-3-methylbutanoyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(303);5-(5-(1-(3-hydroxy-2,2-dimethylpropanoyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(304); (S)-5-(5-(1-(3-hydroxybutanoyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(305);(R)-5-(3-isopropyl-5-(1-(2-(pyrrolidin-2-yl)acetyl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(306); (S)-1-methylpyrrolidin-3-yl4-(2-(5-chloro-1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate(307); 3-chloro-5-(3-isopropyl-5-(1-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)piperidin-4-yl)-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one (308);3-chloro-5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(309);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(310);5-(5-(1-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(313); 5-(5-(1-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(314);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(315);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(316); 5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methoxy-1,4-dimethylpyridin-2(1H)-one(317);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methoxy-1,6-dimethylpyridin-2(1H)-one(318);5-(5-(1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,4-trimethylpyridin-2(1H)-one(319);5-(5-(1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3,6-trimethylpyridin-2(1H)-one(320);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(321);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile(322);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(323); 5-(5-(1-(2-hydroxy-3-methylbutyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(324);5-(5-(1-(2-hydroxy-3,3-dimethylbutyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyridin-2(1H)-one(325);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-methyl-3-(pyrimidin-5-yl)pyridin-2(1H)-one(326);3-chloro-5-(4-fluoro-5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,4-dimethylpyridin-2(1H)-one(327);5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-isobutyl-3-methylpyridin-2(1H)-one(328);1-benzyl-5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-3-methylpyridin-2(1H)-one(329);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-6′-morpholino-[3,3′-bipyridin]-2(1H)-one(330);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-3-(2-methoxypyrimidin-5-yl)-1-methylpyridin-2(1H)-one(331);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1,5′-dimethyl-[3,3′-bipyridin]-2(1H)-one(332);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1,4-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one(333);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (334);N-(5′-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1′-methyl-2′-oxo-1′,2′-dihydro-[3,3′-bipyridin]-6-yl)acetamide(335);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,4′-bipyridin]-2(1H)-one(336);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(2-methylpyrimidin-5-yl)pyridin-2(1H)-one(337);3-(2-cyclopropylpyrimidin-5-yl)-5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methylpyridin-2(1H)-one(338);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one (339);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-3-(3-methoxyphenyl)-1-methylpyridin-2(1H)-one(340);6′-fluoro-5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(341);6′-fluoro-5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1-methyl-[3,3′-bipyridin]-2(1H)-one(342);6′-fluoro-5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,5′-dimethyl-[3,3′-bipyridin]-2(1H)-one(343);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,2′-dimethyl-[3,3′-bipyridin]-2(1H)-one(244);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(345); 5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(346);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(347);5-(3-isopropyl-5-(1-propylpiperidin-4-yl)-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(348);5-(3-isopropyl-5-(1-(2-methoxyethyl)piperidin-4-yl)-1H-indol-2-yl)-1,6′-dimethyl-[3,3′-bipyridin]-2(1H)-one(349);5-(3-isopropyl-5-(1-(2-methoxyethyl)piperidin-4-yl)-1H-indol-2-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one(350);2-(4-(3-isopropyl-2-(5-(methoxymethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(351);2-(4-(3-isopropyl-2-(1-methyl-6-oxo-5-vinyl-1,6-dihydropyridin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide(352); and5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-3-(methoxymethyl)-1-methylpyridin-2(1H)-one(353).
 17. The compound according to claim 1 or a salt thereof, whereinsaid compound is selected from:5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1-methylpyrazin-2(1H)-one(4);6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2-methylpyridazin-3(2H)-one(5);6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2,5-dimethylpyridazin-3(2H)-one(10);6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(11);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(12);6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-2,4,5-trimethylpyridazin-3(2H)-one(17);2-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-4-methylpyridazin-3(2H)-one(18);5-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione(21);2-ethyl-6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-4,5-dimethylpyridazin-3(2H)-one(27);2-(4-(2-(4,6-dimethyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (115);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (116);2-(4-(2-(1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide (118);2-(4-(3-isopropyl-2-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N,N-dimethylacetamide (130);2-(4-(3-isopropyl-2-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-5-yl)piperidin-1-yl)-N-methylacetamide (131);5-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(183);5-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(184);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(185); 5-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one (186);5-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(187);6-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(188);6-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(189);5-(3-isopropyl-5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(190);6-(3-isopropyl-5-(1-methylpiperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(191);6-(3-isopropyl-5-(1-isopropylpiperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(192);6-(3-isopropyl-5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(193);6-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(194);6-(3-isopropyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-indol-2-yl)-2,4,5-trimethylpyridazin-3(2H)-one(203); 6-(3-isopropyl-5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1H-indol-2-yl)-2,4,5-trimethylpyridazin-3(2H)-one (205);6-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-2,4,5-trimethylpyridazin-3(2H)-one(283);6-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(294);5-(5-(1-(dimethylglycyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(295);6-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-2,4-dimethylpyridazin-3(2H)-one(311); and5-(5-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1,3-dimethylpyrazin-2(1H)-one(312).
 18. A method of treating an autoimmune disease or a chronicinflammatory disease, comprising administering to a mammalian patent acompound according to claim 1 or a pharmaceutically acceptable saltthereof, wherein said autoimmune disease or chronic inflammatory diseaseis selected from systemic lupus erythematosus (SLE), rheumatoidarthritis, multiple sclerosis (MS), and Sjögren's syndrome.